Bio

Bio


Dr. Vinicio de Jesus Perez received his MD from the University of Puerto Rico Medical School and completed an internal medicine residency at Massachusetts General Hospital. He completed a fellowship in pulmonary and critical care medicine in Denver, followed by postdoctoral research training at Stanford University. He focused on researching genetic and molecular mechanisms of pulmonary hypertension (PH) and idiopathic pulmonary fibrosis (IPF) and has devoted his clinical practice to diagnosis and management of these conditions. He is presently assistant professor of medicine and staff physician of the Stanford Adult PH Clinic where he trains fellows pursuing careers in PH and IPF. He is principal investigator of a research program with the ultimate goal of identifying new therapeutic targets to treat PH and IPF.

As a medical professional belonging to a minority group, Dr. de Jesus Perez is involved in academic endeavors seeking to improve access of care for patients with disadvantageous ethnic backgrounds and promote diversity in medicine.

Clinical Focus


  • Pulmonary Disease
  • Pulmonary Hypertension
  • Idiopathic Pulmonary Fibrosis
  • Scleroderma Lung Diseases
  • Drug Induced Pulmonary Hypertension
  • LAM

Academic Appointments


Administrative Appointments


  • Faculty Member, Bio-X (2012 - Present)
  • Faculty Member, CHRI (2012 - Present)
  • Assistant Professor of Medicine, Stanford University (2011 - Present)
  • Staff Physician, Adult Pulmonary Hypertension Clinic (2006 - Present)
  • Faculty Member, Stanford Cardiovascular Institute (2011 - Present)

Honors & Awards


  • CHRI Pilot Study on LAM/TSC, Stanford CHRI (2015-2017)
  • AHA Beginning Grant in Aid, American Heart Association (2015-2017)
  • InterMune/Genentech Young Faculty Scholar in Pulmonary Fibrosis, Genentech (2015-2017)
  • Faculty of 1000 Faculty Member of the Year for Respiratory Disorders, Faculty of 1000 (2014)
  • Primary Mentor, Hispanic-Serving Health Professions Schools (2015)
  • Mentor, CHRI postdoctoral award, Stanford Child Health Research Institute (2015-2018)
  • Cournand and Comroe Award (mentor), American Heart Association (2014)
  • Stanford-Karolinska Institute Collaborative Award, Swedish Foundation for International Collaboration (2014-2016)
  • Faculty of 1000 Reviewer of the year, Faculty of 1000 Prime (2013)
  • The Role of Angiogenesis in Lung development, Stanford Child Health Research Institute (2014-2016)
  • Member of the Planning Committee, 2014 Keystone Symposia Series, Keystone Symposia (2013-2015)
  • Fellow, American Heart Association, American Heart Association (2013)
  • Keystone Symposia Fellowship, Keystone Symposia (2013)
  • Distinguished Faculty Fellow, Stanford University (2013)
  • American Lung Association Biomedical Research Grant, American Lung Association (2013-2015)
  • Be HEARD rare disease challenge award, Assay Depot/Sigma (2013-2015)
  • Faculty Member, Faculty Row (2013)
  • Faculty Member, Faculty of 1000, Pulmonary Vascular Diseases (2013)
  • CVI seed grant, Stanford CVI (2013)
  • Pulmonary Hypertension Breakthrough Initiative, CMREF (2012-)
  • Supplemental Award to Outstanding K08, Pulmonary Hypertension Association (2012-2017)
  • Editor, Case Reports in Clinical Medicine (2012-)
  • TRAM award, Translational Research and Applied Medicine Program, Stanford University (2012-2013)
  • Member, Scientific Research Committee, Pulmonary Hypertension Association (2012-)
  • OCT as a novel tool in the diagnosis of PAH, CBIS (2012-2013)
  • Fellow, American College of Chest Physicians (2012)
  • NIH Career Development Award (1 K08 HL105884-01), NIH (7/2012-7/2017)
  • Wall Center Genomics Research Grant, Vera Moulton Wall Center for Pulmonary Vascular Research (2011-2012)
  • Minority Travel Award, ATS (2010)
  • Member-at-large, Cardiopulmonary, Critical Care, Perioperative & Resuscitation Council, American Heart Association (2010-)
  • Scholar, Harold Amos Career Development Award, Robert Wood Johnson Foundation (2010-2014)
  • ATS travel award, ATS (2009)
  • Finalist, BWF award, Burroughs Wellcome Fund (2009)
  • 2008 Professional of the year, Madison Who's who among pofessionals in America (2009)
  • Fellow, Pulmonary Vascular Research Institute (2008)
  • Career Development Program in the Genetics and Genomics of Lung Diseases (K12), NIH (2008)
  • AHA Scientific Sessions 2008 Best Basic Science Abstract, American Heart Association (2008)
  • American Lung Association Career Development Award, American Lung Association (2008)
  • Oak Foundation Grant, Oak Foundation (2008)
  • AHA 2007 Junior Investigator Travel Award, American Heart Association (2007)
  • ATS 2007 Travel award, American Thoracic Society (2007)
  • Who's Who in America, Madison's Who's Who (2007)
  • Finalist, Young Investigator Award, Stanford University Medical Center-Cardiovascular Institute (2007)
  • Who's Who in Medicine in America 2007, Marquis Who's Who in America (2007)
  • American Lung Association Postdoctoral Fellowship Award, American Lung Association (2006)
  • Best Fellow, University of Colorado-Denver (2003)
  • Best Intern in Medicine, Massachusetts General Hospital (2001)
  • Most Promising Young Profesional 2000, El Nuevo Dia (2000)
  • Summa cum Laude-Medicine, University of Puerto Rico (2000)
  • Beta Beta Beta Award, Beta Beta Beta (1996)
  • Summa cum Laude-Biology, University of Puerto Rico (1996)

Boards, Advisory Committees, Professional Organizations


  • Scientific Advisory Council, Pulmonary Hypertension Association (2012 - Present)
  • Member at Large, 3CPR Council, American Heart Association (2013 - Present)
  • Editorial Board, American Journal of Respiratory and Critical Care Medicine (2012 - Present)
  • Editorial Board, Pulmonary Circulation (2013 - Present)
  • Member, 3CPR Early Career Advisory Committee, American Heart Association (2013 - Present)
  • Early Career Committee, American Heart Association (2014 - Present)
  • AHA Diversity Focus Committee, American Heart Association (2014 - Present)
  • PHA Early Diagnosis Campaign, Pulmonary Hypertension Association (2013 - Present)
  • 3CPR Leadership Committee, American Heart Association (2014 - Present)
  • Editorial Board, Faculty of 1000 (2014 - Present)
  • Keystone Symposia Scientific Advisory Board, ad-hoc member, Keystone Symposia (2014 - Present)
  • Primary Mentor, Hispanic-Serving Health Professions Schools (2014 - Present)
  • Member, planning committee, 2016 International PH Conference and Scientific Sessions (2015 - Present)
  • Advisory Board Member, Faculty of 1000 (2014 - Present)
  • Chair, Committee on barriers to PH care for disadvantaged populations, Pulmonary Hypertension Association (2015 - Present)
  • Member at large, Early Diagnosis Committee, Pulmonary Hypertension Association (2013 - Present)

Professional Education


  • Fellowship:Univ Of Colorado (2004) CO
  • Residency:Massachusetts General Hospital (2003) MA
  • Internship:Massachusetts General Hospital (2001) MA
  • Board Certification: Critical Care Medicine, American Board of Internal Medicine (2007)
  • Board Certification: Pulmonary Disease, American Board of Internal Medicine (2006)
  • Fellowship:Stanford University Medical Center (2006) CA
  • Medical Education:University Of Puerto Rico (2000) PR
  • MD, Stanford University, Pulmonary/CCM (2006)
  • MD, University of Colorado-Denver, Pulmonary/CCM (2004)
  • MD, Massachussetts General Hospital, Internal Medicine (2003)
  • MD, University of Puerto Rico, Medicine (2000)
  • BS, University of Puerto Rico, Biology (1996)

Community and International Work


  • Stanford Career Development Program in Omics of Lung Diseases, Stanford University

    Topic

    Pulmonary Genomics

    Location

    California

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • European Respiratory Society

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • National Scleroderma Foundation

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Pulmonary Fibrosis Foundation (PFF)

    Topic

    Pulmonary Fibrosis

    Populations Served

    IPF patients

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Pulmonary Hypertension Educational Committee

    Topic

    Pulmonary Hypertension

    Partnering Organization(s)

    Pulmonary Hypertension Association

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Latin American PH Society

    Populations Served

    Latin-american PH patients

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Pulmonary Vascular Research Institute

    Topic

    Pulmonary Hypertension

    Populations Served

    PH patients

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • North American Vascular Biology Society

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • American College of Chest Physicians

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • American Thoracic Society

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • American Society of Cell Biology

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • American Heart Association

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • National PH Association

    Topic

    Pulmonary Hypertension

    Populations Served

    Patientsd and families with PH

    Location

    US

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Current Research and Scholarly Interests


My work is aimed at understanding the molecular mechanisms involved in the development and progression of pulmonary arterial hypertension (PAH). I am interested in understanding the role that the BMP and Wnt pathways play in regulating functions of pulmonary endothelial and smooth muscle cells both in health and disease.

Teaching

2014-15 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Activation of the Wnt/Planar Cell Polarity Pathway Is Required for Pericyte Recruitment during Pulmonary Angiogenesis AMERICAN JOURNAL OF PATHOLOGY Yuan, K., Orcholski, M. E., Panaroni, C., Shuffle, E. M., Huang, N. F., Jiang, X., Tian, W., Vladar, E. K., Wang, L., Nicolls, M. R., Wu, J. Y., Perez, V. A. 2015; 185 (1): 69-84

    Abstract

    Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial-pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G-coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward endothelium via live-imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. PAH pericytes had reduced expression of frizzled 7 (Fzd7) and cdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes in vitro and in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial-pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH.

    View details for DOI 10.1016/j.ajpath.2014.09.013

    View details for Web of Science ID 000346887200008

  • Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1 JOURNAL OF CLINICAL INVESTIGATION Ali, Z. A., Perez, V. D., Yuan, K., Orcholski, M., Pan, S., Qi, W., Chopra, G., Adams, C., Kojima, Y., Leeper, N. J., Qu, X., Zaleta-Rivera, K., Kato, K., Yamada, Y., Oguri, M., Kuchinsky, A., Hazen, S. L., Jukema, J. W., Ganesh, S. K., Nabe, E. G., Channon, K., Leon, M. B., Charest, A., Quertermous, T., Ashley, E. A. 2014; 124 (12): 5159-5174

    Abstract

    Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.

    View details for DOI 10.1172/JCI77484

    View details for Web of Science ID 000345677200011

    View details for PubMedID 25401476

  • Pumping it up! Angiogenesis and muscle deconditioning in pulmonary hypertension. American journal of respiratory and critical care medicine de Jesus Perez, V. A. 2014; 190 (3): 250-251

    View details for DOI 10.1164/rccm.201406-1163ED

    View details for PubMedID 25084260

  • Targeting the Wnt signaling pathways in pulmonary arterial hypertension. Drug discovery today de Jesus Perez, V., Yuan, K., Alastalo, T., Spiekerkoetter, E., Rabinovitch, M. 2014; 19 (8): 1270-1276

    Abstract

    Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease.

    View details for DOI 10.1016/j.drudis.2014.06.014

    View details for PubMedID 24955837

  • Whole-Exome Sequencing Reveals TopBP1 as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Perez, V. A., Yuan, K., Lyuksyutova, M. A., Dewey, F., Orcholski, M. E., Shuffle, E. M., Mathur, M., Yancy, L., Rojas, V., Li, C. G., Cao, A., Alastalo, T., Khazeni, N., Cimprich, K. A., Butte, A. J., Ashley, E., Zamanian, R. T. 2014; 189 (10): 1260-1272

    Abstract

    Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. While mutations in the bone morphogenetic receptor (BMPR) 2 are found in 80% of heritable and ±15% of IPAH patients, their low penetrance (±20%) suggests that other as-yet unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH but whether WES can also accelerate gene discovery in IPAH remains unknown. Objectives: To determine whether WES can help identify novel gene modifiers in IPAH patients. Methods and Measurements: Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated IPAH patients lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. Main Results: A total of 10 genes were identified as high priority candidates. Our top hit was TopBP1, a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from IPAH patients. While TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival. Conclusions: WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibly to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.

    View details for DOI 10.1164/rccm.201310-17490C

    View details for Web of Science ID 000336017200018

  • Loss-of BMPR2 is Associated With Abnormal DNA Repair in Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Li, M., Vattulainen, S., Aho, J., Orcholski, M., Rojas, V., Yuan, K., Helenius, M., Taimen, P., Myllykangas, S., De Jesus Perez, V., Koskenvuo, J. W., Alastalo, T. P. 2014

    Abstract

    Rationale: Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic for pulmonary arterial hypertension (PAH). While a phenotypic switch in pulmonary endothelial cells (EC) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. Methods: Bioinfomatics approach, patient samples and in vitro experiments were utilized. Results: By combining a meta-analysis of human iPAH-associated gene-expression microarrays and a unique gene expression profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss-of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from iPAH patients and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control as excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified BRCA1 as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. Conclusions: We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

    View details for DOI 10.1165/rcmb.2013-0349OC

    View details for PubMedID 24433082

  • Loss of adenomatous poliposis coli-a3 integrin interaction promotes endothelial apoptosis in mice and humans. Circulation research de Jesus Perez, V. A., Yuan, K., Orcholski, M. E., Sawada, H., Zhao, M., Li, C. G., Tojais, N. F., Nickel, N., Rajagopalan, V., Spiekerkoetter, E., Wang, L., Dutta, R., Bernstein, D., Rabinovitch, M. 2012; 111 (12): 1551-1564

    Abstract

    Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/?-catenin pathway, we proposed that ?-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH.This study aims to establish the role of ?-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury.To assess the impact of ?-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive ?-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the ?3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC.We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.

    View details for DOI 10.1161/CIRCRESAHA.112.267849

    View details for PubMedID 23011394

  • BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways JOURNAL OF CELL BIOLOGY Perez, V. A., Ali, Z., Alastalo, T., Ikeno, F., Sawada, H., Lai, Y., Kleisli, T., Spiekerkoetter, E., Qu, X., Rubinos, L. H., Ashley, E., Amieva, M., Dedhar, S., Rabinovitch, M. 2011; 192 (1): 171-188

    Abstract

    We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-?-catenin (?C) and Wnt-planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces ?C transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via ?4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds ?C without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent ?C activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2-mediated tandem activation of Wnt-?C and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.

    View details for DOI 10.1083/jcb.201008060

    View details for Web of Science ID 000287778600015

    View details for PubMedID 21220513

  • Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways JOURNAL OF CELL BIOLOGY Perez, V. A., Alastalo, T., Wu, J. C., Axelrod, J. D., Cooke, J. P., Amieva, M., Rabinovitch, M. 2009; 184 (1): 83-99

    Abstract

    Mutations in bone morphogenetic protein (BMP) receptor II (BMPRII) are associated with pulmonary artery endothelial cell (PAEC) apoptosis and the loss of small vessels seen in idiopathic pulmonary arterial hypertension. Given the low penetrance of BMPRII mutations, abnormalities in other converging signaling pathways may be necessary for disease development. We hypothesized that BMPRII supports normal PAEC function by recruiting Wingless (Wnt) signaling pathways to promote proliferation, survival, and motility. In this study, we report that BMP-2, via BMPRII-mediated inhibition of GSK3-beta, induces beta-catenin (beta-C) accumulation and transcriptional activity necessary for PAEC survival and proliferation. At the same time, BMP-2 mediates phosphorylated Smad1 (pSmad1) or, with loss of BMPRII, pSmad3-dependent recruitment of Disheveled (Dvl) to promote RhoA-Rac1 signaling necessary for motility. Finally, using an angiogenesis assay in severe combined immunodeficient mice, we demonstrate that both beta-C- and Dvl-mediated RhoA-Rac1 activation are necessary for vascular growth in vivo. These findings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2-mediated angiogenesis.

    View details for DOI 10.1083/jcb.200806049

    View details for Web of Science ID 000262867000010

    View details for PubMedID 19139264

  • Perlecan Heparan Sulfate Deficiency Impairs Pulmonary Vascular Development and Attenuates Hypoxic Pulmonary Hypertension. Cardiovascular research Chang, Y. T., Tseng, C. N., Tannenberg, P., Eriksson, L., Yuan, K., de Jesus Perez, V. A., Lundberg, J., Lengquist, M., Botusan, I. R., Catrina, S. B., Tran, P. K., Hedin, U., Tran-Lundmark, K. 2015

    Abstract

    Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH.In normoxia, Hspg2(r3/r3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(r3/r3) compared to wild-type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(r3/r3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(r3/r3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(r3/r3) compared to wild-type.Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.

    View details for DOI 10.1093/cvr/cvv143

    View details for PubMedID 25952902

  • Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension. American journal of physiology. Lung cellular and molecular physiology Helenius, M. H., Vattulainen, S., Orcholski, M., Aho, J., Komulainen, A., Taimen, P., Wang, L., de Jesus Perez, V. A., Koskenvuo, J. W., Alastalo, T. P. 2015: ajplung.00340.2014

    Abstract

    Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signalling pathways, which consists of extracellular nucleotide and nucleoside mediated cell signalling through specific receptors, are known to be important regulators of vascular tone and remodelling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzyme on EC surface is E-NTPDase1/CD39, which hydrolyses ATP and ADP to AMP. We used histological samples from patients and healthy donors, radioisotope labelled substrates to measure ecto-enzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH patients' lungs demonstrated that CD39 was significantly down-regulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis resistant pulmonary arterial endothelial cells, and promoted a microenvironment that induced vascular smooth muscle cell migration. We also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. We conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodelling in PAH and could represent a novel target for therapy.

    View details for DOI 10.1152/ajplung.00340.2014

    View details for PubMedID 25820525

  • Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Jiang, X., Nguyen, T. T., Tian, W., Sung, Y. K., Yuan, K., Qian, J., Rajadas, J., Sallenave, J. M., Nickel, N. P., de Jesus Perez, V., Rabinovitch, M., Nicolls, M. R. 2015

    Abstract

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.

    View details for DOI 10.1111/ajt.13189

    View details for PubMedID 25727073

  • Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Spruijt, O. A., Denault, A. Y., Mercier, O., Brunner, N., Furman, D., Fadel, E., Bogaard, H. J., Schnittger, I., Vrtovec, B., Wu, J. C., de Jesus Perez, V., Vonk-Noordegraaf, A., Zamanian, R. T. 2015

    Abstract

    This study sought to determine whether a simple score combining indexes of right ventricular (RV) function and right atrial (RA) size would offer good discrimination of outcome in patients with pulmonary arterial hypertension (PAH).Identifying a simple score of outcome could simplify risk stratification of patients with PAH and potentially lead to improved tailored monitoring or therapy.We recruited patients from both Stanford University (derivation cohort) and VU University Medical Center (validation cohort). The composite endpoint for the study was death or lung transplantation. A Cox proportional hazard with bootstrap CI adjustment model was used to determine independent correlates of death or transplantation. A predictive score was developed using the beta coefficients of the multivariable models.For the derivation cohort (n = 95), the majority of patients were female (79%), average age was 43 ± 11 years, mean pulmonary arterial pressure was 54 ± 14 mm Hg, and pulmonary vascular resistance index was 25 ± 12 Wood units m(2). Over an average follow-up of 5 years, the composite endpoint occurred in 34 patients, including 26 deaths and 8 patients requiring lung transplant. On multivariable analysis, RV systolic dysfunction grade (hazard ratio [HR]: 3.4 per grade; 95% confidence interval [CI]: 2.0 to 7.8; p < 0.001), severe RA enlargement (HR: 3.0; 95% CI: 1.3 to 8.1; p = 0.009), and systemic blood pressure <110 mm Hg (HR: 3.3; 95% CI: 1.5 to 9.4; p < 0.001) were independently associated with outcome. A right heart (RH) score constructed on the basis of these 3 parameters compared favorably with the National Institutes of Health survival equation (0.88; 95% CI: 0.79 to 0.94 vs. 0.60; 95% CI: 0.49 to 0.71; p < 0.001) but was not statistically different than the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score c-statistic of 0.80 (95% CI: 0.69 to 0.88) with p = 0.097. In the validation cohort (n = 87), the RH score remained the strongest independent correlate of outcome.In patients with prevalent PAH, a simple RH score may offer good discrimination of long-term outcome.

    View details for DOI 10.1016/j.jcmg.2014.12.029

    View details for PubMedID 25981508

  • Current Clinical Management of Pulmonary Arterial Hypertension CIRCULATION RESEARCH Zamanian, R. T., Kudelko, K. T., Sung, Y. K., Perez, V. D., Liu, J., Spiekerkoetter, E. 2014; 115 (1): 131-147

    Abstract

    During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.

    View details for DOI 10.1161/CIRCRESAHA.115.303827

    View details for Web of Science ID 000337738900016

  • Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery. Pulmonary circulation Brunner, N., de Jesus Perez, V. A., Richter, A., Haddad, F., Denault, A., Rojas, V., Yuan, K., Orcholski, M., Liao, X. 2014; 4 (1): 10-24

    Abstract

    Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

    View details for DOI 10.1086/674885

    View details for PubMedID 25006417

  • Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension JOURNAL OF EXPERIMENTAL MEDICINE Sawada, H., Saito, T., Nickel, N. P., Alastalo, T., Glotzbach, J. P., Chan, R., Haghighat, L., Fuchs, G., Januszyk, M., Cao, A., Lai, Y., Perez, V. D., Kim, Y., Wang, L., Chen, P., Spiekerkoetter, E., Mitani, Y., Gurtner, G. C., Sarnow, P., Rabinovitch, M. 2014; 211 (2): 263-280

    Abstract

    Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2?), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor ? (GM-CSFR?)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

    View details for DOI 10.1084/jem.20111741

    View details for Web of Science ID 000331281600008

  • Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery Pulmonary Circulation Brunner, N. W. 2014; 4 (1): 10-24

    View details for DOI 10.1086/674885

  • FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

    Abstract

    Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

    View details for DOI 10.1172/JCI65592

    View details for PubMedID 23867624

  • Understanding the pharmacokinetics of oral treprostinil in patients with pulmonary arterial hypertension. Journal of cardiovascular pharmacology de Jesus Perez, V. A. 2013; 61 (6): 471-473

    View details for DOI 10.1097/FJC.0b013e318294980e

    View details for PubMedID 23575261

  • MicroRNAs: promising therapeutic targets for the treatment of pulmonary arterial hypertension EXPERT OPINION ON THERAPEUTIC TARGETS Yuan, K., Orcholski, M., Tian, X., Liao, X., Perez, V. A. 2013; 17 (5): 557-564

    Abstract

    MicroRNAs (miRNAs) are small noncoding RNAs that not only regulate gene expression during normal development but can also be active players in several diseases. To date, several studies have demonstrated a possible role for specific miRNAs in the regulation of pulmonary vascular homeostasis suggesting that novel therapeutic agents which target these modulators of gene expression could serve to treat pulmonary arterial hypertension (PAH). AREAS COVERED: The characterization of miRNA-mediated gene modulation in the pulmonary circulation is expanding very rapidly. This review summarizes current relevant findings on the role of miRNAs in the pathogenesis of PAH and expands on the potential use of agents that target these molecules as future disease-modifying therapies. EXPERT OPINION: Further understanding of miRNA biology and function in the pulmonary circulation will serve to further enhance our understanding of their contribution to the pathogenesis of PAH. The implementation of a systems biology approach will help accelerate the discovery of miRNAs that influence angiogenesis and cellular responses to vascular injury. Experimental characterization of these miRNAs using in vitro and in vivo methods will be required to validate the biological roles of these miRNAs prior to the consideration of their use as therapeutic targets in future clinical trials.

    View details for DOI 10.1517/14728222.2013.765863

    View details for Web of Science ID 000317935400008

  • Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus. Journal of molecular medicine (Berlin, Germany) Jiang, X., Hsu, J. L., Tian, W., Yuan, K., Olcholski, M., de Jesus Perez, V., Semenza, G. L., Nicolls, M. R. 2013

    Abstract

    Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel-Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL-haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1? deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1? normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83 % of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75 % of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1? in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1? expression has the prospect of offering several novel therapeutic effects to transplant recipients.Microvascular loss and prolonged ischemia occurs with acute rejection. Von Hippel-Lindau (VHL) protein controls hypoxia inducible factors (HIFs). In tracheal allografts, VHL haplodeficient Tie2 cells promote neovascularization. Reduced transplant ischemia limits Aspergillus invasion.

    View details for PubMedID 23797537

  • FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension Journal of Clinical Investigation Spiekerkoetter, E. 2013; 123 (8): 3600-13
  • MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells. Endocrinology Liao, X. B., Zhang, Z. Y., Yuan, K., Liu, Y., Feng, X., Cui, R. R., Hu, Y. R., Yuan, Z. S., Gu, L., Li, S. J., Mao, D. A., Lu, Q., Zhou, X. M., de Jesus Perez, V. A., Yuan, L. Q. 2013

    Abstract

    Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with ?-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression and mineralized nodule formation. Conversely, the knockdown of miR-133a using a miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion and Runx2 expression. Runx2 was identified as a direct target of miR-133a by co-transfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3`-UTR sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2 knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.

    View details for PubMedID 23798596

  • A case of recurrent pericardial constriction presenting with severe pulmonary hypertension Pulmonary Circulation Nathan Brunner, Krithika Ramachandran, Kristina T. Kudelko, Yon K. Sung, Edda Spiekerkoetter, Phillip C. Yang, Roham T. Zamanian, Vinicio de Jesus Perez 2013; 3 (2): 436-439
  • Effectiveness of YouTube as a Source of Medical Information on Heart Transplantation. Interactive journal of medical research Chen, H., Hu, Z., Zheng, X., Yuan, Z., Xu, Z., Yuan, L., Perez, V. A., Yuan, K., Orcholski, M., Liao, X. 2013; 2 (2)

    Abstract

    In this digital era, there is a growing tendency to use the popular Internet site YouTube as a new electronic-learning (e-learning) means for continuing medical education. Heart transplantation (HTx) remains the most viable option for patients with end-stage heart failure or severe coronary artery disease. There are plenty of freely accessible YouTube videos providing medical information about HTx.The aim of the present study is to determine the effectiveness of YouTube as an e-learning source on HTx.In order to carry out this study, YouTube was searched for videos uploaded containing surgical-related information using the four keywords: (1) "heart transplantation", (2) "cardiac transplantation", (3) "heart transplantation operation", and (4) "cardiac transplantation operation". Only videos in English (with comments or subtitles in English language) were included. Two experienced cardiac surgeons watched each video (N=1800) and classified them as useful, misleading, or recipients videos based on the HTx-relevant information. The kappa statistic was used to measure interobserver variability. Data was analyzed according to six types of YouTube characteristics including "total viewership", "duration", "source", "days since upload", "scores" given by the viewers, and specialized information contents of the videos.A total of 342/1800 (19.00%) videos had relevant information about HTx. Of these 342 videos, 215 (62.8%) videos had useful information about specialized knowledge, 7/342 (2.0%) were found to be misleading, and 120/342 (35.1%) only concerned recipients' individual issues. Useful videos had 56.09% of total viewership share (2,175,845/3,878,890), whereas misleading had 35.47% (1,375,673/3,878,890). Independent user channel videos accounted for a smaller proportion (19% in total numbers) but might have a wider impact on Web viewers, with the highest mean views/day (mean 39, SD 107) among four kinds of channels to distribute HTx-related information.YouTube videos on HTx benefit medical professionals by providing a substantial amount of information. However, it is a time-consuming course to find high-quality videos. More authoritative videos by trusted sources should be posted for dissemination of reliable information. With an improvement of ranking system and content providers in future, YouTube, as a freely accessible outlet, will help to meet the huge informational needs of medical staffs and promote medical education on HTx.

    View details for DOI 10.2196/ijmr.2669

    View details for PubMedID 24263225

  • Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension. American journal of cardiology de Jesus Perez, V. A., Rosenzweig, E., Rubin, L. J., Poch, D., Bajwa, A., Park, M., Jain, M., Bourge, R. C., Kudelko, K., Spiekerkoetter, E., Liu, J., Hsi, A., Zamanian, R. T. 2012; 110 (10): 1546-1550

    Abstract

    Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

    View details for DOI 10.1016/j.amjcard.2012.07.012

    View details for PubMedID 22853986

  • The Intersection of Genes and Environment Development of Pulmonary Arterial Hypertension in a Patient With Hereditary Hemorrhagic Telangiectasia and Stimulant Exposure CHEST Ayala, E., Kudelko, K. T., Haddad, F., Zamanian, R. T., Perez, V. d. 2012; 141 (6): 1598-1600

    Abstract

    Pulmonary arterial hypertension (PAH) is a rare complication of hereditary hemorrhagic telangiectasia (HHT). The triggers that promote the development of PAH in HHT remain poorly understood. We present the case of a 45-year-old woman with decompensated right-sided heart failure secondary to newly diagnosed PAH. The clinical diagnosis of HHT was confirmed on the basis of recurrent spontaneous epistaxis, multiple typical mucocutaneous telangiectasia, and the presence of pulmonary arteriovenous malformation. There was also a suggestive family history. The patient was discovered to have active and extensive stimulant abuse in addition to HHT. We concluded that there may be a temporal relationship between exposure to stimulants and development of PAH in a host with underlying gene mutation. This case highlights the paradigm of PAH development after environmental exposure in a genetically susceptible host.

    View details for DOI 10.1378/chest.11-1402

    View details for Web of Science ID 000305039300054

    View details for PubMedID 22670022

  • Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction Pulmonary Circulation de Jesus Perez, V., Haddad, F, Zamanian RT 2012; 2 (2): 163
  • Development of a recurrent pleural effusion in a patient with pulmonary arterial hypertension treated with imatinib Case Reports in Clinical Medicine Olga M. Fortenko, Lana Melendres-Groves, Alice Richter, Xiaobo Liao, Edda Spiekerkoetter, Roham Zamanian, Vinicio A. De Jesus Perez 2012; 1 (2): 38-41
  • Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension CIRCULATION-HEART FAILURE Haddad, F., Peterson, T., Fuh, E., Kudelko, K. T., Perez, V. D., Skhiri, M., Vagelos, R., Schnittger, I., Denault, A. Y., Rosenthal, D. N., Doyle, R. L., Zamanian, R. T. 2011; 4 (6): 692-699

    Abstract

    Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ?136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

    View details for DOI 10.1161/CIRCHEARTFAILURE.110.949933

    View details for Web of Science ID 000297166100008

    View details for PubMedID 21908586

  • Disruption of PPAR gamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival JOURNAL OF CLINICAL INVESTIGATION Alastalo, T., Li, M., Perez, V. D., Pham, D., Sawada, H., Wang, J. K., Koskenvuo, M., Wang, L., Freeman, B. A., Chang, H. Y., Rabinovitch, M. 2011; 121 (9): 3735-3746

    Abstract

    Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPAR? and ?-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPAR?/?-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPAR? in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.

    View details for DOI 10.1172/JCI43382

    View details for Web of Science ID 000294753700038

    View details for PubMedID 21821917

  • Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies PROGRESS IN CARDIOVASCULAR DISEASES Haddad, F., Kudelko, K., Mercier, O., Vrtovec, B., Zamanian, R. T., Perez, V. D. 2011; 54 (2): 154-167

    Abstract

    Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

    View details for DOI 10.1016/j.pcad.2011.06.003

    View details for Web of Science ID 000294880400009

    View details for PubMedID 21875514

  • Incidence, Correlates, and Consequences of Acute Kidney Injury in Patients With Pulmonary Arterial Hypertension Hospitalized With Acute Right-Side Heart Failure JOURNAL OF CARDIAC FAILURE Haddad, F., Fuh, E., Peterson, T., Skhiri, M., Kudelko, K. T., Perez, V. D., Winkelmayer, W. C., Doyle, R. L., Chertow, G. M., Zamanian, R. T. 2011; 17 (7): 533-539

    Abstract

    Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH).We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2).AKI is relatively common in patients with PAH and associated with a short-term risk of death.

    View details for DOI 10.1016/j.cardfail.2011.03.003

    View details for Web of Science ID 000292368500002

    View details for PubMedID 21703524

  • Chronic Thromboembolic Pulmonary Hypertension NEW ENGLAND JOURNAL OF MEDICINE Perez, V. A., Zamanian, R. T. 2011; 364 (17): 1677-1677

    View details for Web of Science ID 000289940400022

    View details for PubMedID 21524224

  • Disruption of the Apelin-APJ System Worsens Hypoxia-Induced Pulmonary Hypertension ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chandra, S. M., Razavi, H., Kim, J., Agrawal, R., Kundu, R. K., Perez, V. D., Zamanian, R. T., Quertermous, T., Chun, H. J. 2011; 31 (4): 814-U212

    Abstract

    The G-protein-coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH).We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Micro-computed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2 (KLF2), a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and KLF2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls.These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.

    View details for DOI 10.1161/ATVBAHA.110.219980

    View details for Web of Science ID 000288437800017

    View details for PubMedID 21233449

  • Making Sense of the Estrogen Paradox in Pulmonary Arterial Hypertension American Journal of Respiratory and Critical Care Medicine vinicio de jesus perez 2011; 184: 629
  • Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. International journal of clinical practice. Supplement de Jesus Perez, V., Kudelko, K., Snook, S., Zamanian, R. T. 2011: 8-10

    Abstract

    Since the identification of the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs and toxins nearly fifty years ago, the expanding landscape of available pharmaceuticals and illicit drugs is further fueling this association. While some causative agents in drugs and toxins associated PAH (D&T-APAH) have been identified, little is known about the exact biology and clinical implications of the disease. In this review, we discuss the historical evidence that links PAH with exposure to anorexinogens, cocaine, and methamphetamines and concentrate on what is known about potential pathogenesis, clinical manifestations, and current management. We conclude that future research should focus on studies looking at clinical outcome and susceptibility factors.

    View details for DOI 10.1111/j.1742-1241.2010.02606.x

    View details for PubMedID 21176010

  • Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075

    Abstract

    We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

    View details for DOI 10.1016/j.healun.2010.04.023

    View details for PubMedID 20627625

  • Cholinergic Modulation of Angiogenesis: Role of the 7 Nicotinic Acetylcholine Receptor JOURNAL OF CELLULAR BIOCHEMISTRY Wu, J. C., Chruscinski, A., Perez, V. A., Singh, H., Pitsiouni, M., Rabinovitch, M., Utz, P. J., Cooke, J. P. 2009; 108 (2): 433-446

    Abstract

    Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except alpha(2), alpha(4), gamma, and delta in four different types of ECs. Using siRNA methodology, we found that the alpha(7) nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The alpha(9) and alpha(7) nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the alpha(7) nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis.

    View details for DOI 10.1002/jcb.22270

    View details for Web of Science ID 000270438000012

    View details for PubMedID 19623583

  • S100A4 and Bone Morphogenetic Protein-2 Codependently Induce Vascular Smooth Muscle Cell Migration via Phospho-Extracellular Signal-Regulated Kinase and Chloride Intracellular Channel 4 CIRCULATION RESEARCH Spiekerkoetter, E., Guignabert, C., Perez, V. D., Alastalo, T., Powers, J. M., Wang, L., Lawrie, A., Ambartsumian, N., Schmidt, A., Berryman, M., Ashley, R. H., Rabinovitch, M. 2009; 105 (7): 639-U37

    Abstract

    S100A4/Mts1 is implicated in motility of human pulmonary artery smooth muscle cells (hPASMCs), through an interaction with the RAGE (receptor for advanced glycation end products).We hypothesized that S100A4/Mts1-mediated hPASMC motility might be enhanced by loss of function of bone morphogenetic protein (BMP) receptor (BMPR)II, observed in pulmonary arterial hypertension.Both S100A4/Mts1 (500 ng/mL) and BMP-2 (10 ng/mL) induce migration of hPASMCs in a novel codependent manner, in that the response to either ligand is lost with anti-RAGE or BMPRII short interference (si)RNA. Phosphorylation of extracellular signal-regulated kinase is induced by both ligands and is required for motility by inducing matrix metalloproteinase 2 activity, but phospho-extracellular signal-regulated kinase 1/2 is blocked by anti-RAGE and not by BMPRII short interference RNA. In contrast, BMPRII short interference RNA, but not anti-RAGE, reduces expression of intracellular chloride channel (CLIC)4, a scaffolding molecule necessary for motility in response to S100A4/Mts1 or BMP-2. Reduced CLIC4 expression does not interfere with S100A4/Mts1 internalization or its interaction with myosin heavy chain IIA, but does alter alignment of myosin heavy chain IIA and actin filaments creating the appearance of vacuoles. This abnormality is associated with reduced peripheral distribution and/or delayed activation of RhoA and Rac1, small GTPases required for retraction and extension of lamellipodia in motile cells.Our studies demonstrate how a single ligand (BMP-2 or S100A4/Mts1) can recruit multiple cell surface receptors to relay signals that coordinate events culminating in a functional response, ie, cell motility. We speculate that this carefully controlled process limits signals from multiple ligands, but could be subverted in disease.

    View details for DOI 10.1161/CIRCRESAHA.109.205120

    View details for Web of Science ID 000270150800006

    View details for PubMedID 19713532

  • Angina Associated With Left Main Coronary Artery Compression in Pulmonary Hypertension JOURNAL OF HEART AND LUNG TRANSPLANTATION Perez, V. A., Haddad, F., Vagelos, R. H., Fearon, W., Feinstein, J., Zamanian, R. T. 2009; 28 (5): 527-530

    Abstract

    Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

    View details for DOI 10.1016/j.healun.2008.12.008

    View details for Web of Science ID 000266171400021

    View details for PubMedID 19416787

  • An antiproliferative BMP-2/PPAR gamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension JOURNAL OF CLINICAL INVESTIGATION Hansmann, G., de Jesus Perez, V. A., Alastalo, T., Alvira, C. M., Guignabert, C., Bekker, J. M., Schellong, S., Urashima, T., Wang, L., Morrell, N. W., Rabinovitch, M. 2008; 118 (5): 1846-1857

    Abstract

    Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARgamma and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARgamma that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARgamma agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPARgamma antagonist, and PASMCs isolated from PPARgamma- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARgamma, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARgamma in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARgamma-mediated events could protect against PAH, and PPARgamma agonists may reverse PAH in patients with or without BMP-RII dysfunction.

    View details for DOI 10.1172/JCI32503

    View details for Web of Science ID 000255490100028

    View details for PubMedID 18382765

  • Coexistence of Primary adenocarcinoma of the lung and Tsukamurella pneumonia: a case report and review of the literature Journal of Medical Case Reports de Jesus Perez, V., Swigris J, Ruoss, S 2008; 207 (2)
  • Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation CIRCULATION Hansmann, G., Wagner, R. A., Schellong, S., Perez, V. A., Urashima, T., Wang, L., Sheikh, A. Y., Suen, R. S., Stewart, D. J., Rabinovitch, M. 2007; 115 (10): 1275-1284

    Abstract

    Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone).We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice.We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.

    View details for DOI 10.1161/CIRCULATIONAHA.106.663120

    View details for Web of Science ID 000244864100017

    View details for PubMedID 17339547

Footer Links:

Stanford Medicine Resources: