Seema Dangwal

All Publications

• Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction. Circulation Schimmel, K., Jung, M., Foinquinos, A., San José, G., Beaumont, J., Bock, K., Grote-Levi, L., Xiao, K., Bär, C., Pfanne, A., Just, A., Zimmer, K., Ngoy, S., López, B., Ravassa, S., Samolovac, S., Janssen-Peters, H., Remke, J., Scherf, K., Dangwal, S., Piccoli, M. T., Kleemiss, F., Kreutzer, F. P., Kenneweg, F., Leonardy, J., Hobuß, L., Santer, L., Do, Q. T., Geffers, R., Braesen, J. H., Schmitz, J., Brandenberger, C., Müller, D. N., Wilck, N., Kaever, V., Bähre, H., Batkai, S., Fiedler, J., Alexander, K. M., Wertheim, B. M., Fisch, S., Liao, R., Diez, J., González, A., Thum, T. 2020

  Abstract

  Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis. Methods: Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression. In vitro findings were confirmed in vivo, using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing. Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective anti-fibrotic molecules both in vitro and in vivo leading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds. Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

  View details for DOI 10.1161/CIRCULATIONAHA.119.042559

  View details for PubMedID 31948273

• Preclinical development of a miR-132 inhibitor for heart failure treatment. Nature communications Foinquinos, A., Batkai, S., Genschel, C., Viereck, J., Rump, S., Gyöngyösi, M., Traxler, D., Riesenhuber, M., Spannbauer, A., Lukovic, D., Weber, N., Zlabinger, K., Ha?imbegovi?, E., Winkler, J., Fiedler, J., Dangwal, S., Fischer, M., Roche, J., Wojciechowski, D., Kraft, T., Garamvölgyi, R., Neitzel, S., Chatterjee, S., Yin, X., Bär, C., Mayr, M., Xiao, K., Thum, T. 2020; 11 (1): 633

  Abstract

  Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

  View details for DOI 10.1038/s41467-020-14349-2

  View details for PubMedID 32005803

  View details for PubMedCentralID PMC6994493

• Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers. Diabetes Theocharidis, G., Baltzis, D., Roustit, M., Tellechea, A., Dangwal, S., Khetani, R. S., Shu, B., Zhao, W., Fu, J., Bhasin, S., Kafanas, A., Hui, D., Sui, S. H., Patsopoulos, N. A., Bhasin, M., Veves, A. 2020

  Abstract

  Non-healing diabetic foot ulceration (DFU) is characterized by low grade chronic inflammation, both locally and systemically. We prospectively followed a group of DFU patients who either healed or developed non-healing chronic DFU. Serum and forearm skin analysis, both at protein expression and transcriptomic level, indicated that increased expression of factors such as IFN?, VEGF and sVCAM-1 were associated with DFU healing. Furthermore, foot skin single-cell RNA-seq analysis showed multiple fibroblast cell clusters and increased inflammation in the dorsal skin of Diabetes Mellitus (DM) patients and DFU specimens when compared to controls. In addition, in myeloid cells of DM and DFU patients upstream regulator analysis, we observed inhibition of IL-13 and IFN? and dysregulation of biological processes that included cell movement of monocytes, migration of dendritic cells and chemotaxis of antigen presenting cells pointing to an impaired migratory profile of immune cells in diabetic skin. The SLCO2A1 and CYP1A1 genes, which were up-regulated at the forearm of Non-Healers, were mainly expressed by the vascular endothelial cell cluster almost exclusively in DFU indicating a potential important role in wound healing. These results from integrated protein and transcriptome analyses identified individual genes and pathways that can potentially be targeted for enhancing DFU healing.

  View details for DOI 10.2337/db20-0188

  View details for PubMedID 32763913

• Gene Signatures to Distinguish Amyloid Cardiomyopathy Risk in Multiple Myeloma Patients Jha, A., Morgado, I., Lee, D. J., Alexander, K., Tsai, C., Schimmel, K., Ward, J., Witteles, R., Liedtke, M., Liao, R., Dangwal, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800441

• Prenatal Exposure of Cigarette Smoke Impacts Cardiac Regeneration Schimmel, K., Morgado, I., Tsai, C., Evangelisti, A., Fisch, S., Ngoy, S., Lee, D., Dangwal, S., Alexander, K., Ward, J. E., Liao, R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000511467800423

• Alteration in ventricular pressure stimulates cardiac repair and remodeling. Journal of molecular and cellular cardiology Unno, K., Oikonomopoulos, A., Fujikawa, Y., Okuno, Y., Narita, S., Kato, T., Hayashida, R., Kondo, K., Shibata, R., Murohara, T., Yang, Y., Dangwal, S., Sereti, K. I., Yiling, Q., Johnson, K., Jha, A., Sosnovik, D. E., Fann, Y., Liao, R. 2019

  Abstract

  The mammalian heart undergoes complex structural and functional remodeling to compensate for stresses such as pressure overload. While studies suggest that, at best, the adult mammalian heart is capable of very limited regeneration arising from the proliferation of existing cardiomyocytes, how myocardial stress affects endogenous cardiac regeneration or repair is unknown. To define the relationship between left ventricular afterload and cardiac repair, we induced left ventricle pressure overload in adult mice by constriction of the ascending aorta (AAC). One week following AAC, we normalized ventricular afterload in a subset of animals through removal of the aortic constriction (de-AAC). Subsequent monitoring of cardiomyocyte cell cycle activity via thymidine analog labeling revealed that an acute increase in ventricular afterload induced cardiomyocyte proliferation. Intriguingly, a release in ventricular overload (de-AAC) further increases cardiomyocyte proliferation. Following both AAC and de-AAC, thymidine analog-positive cardiomyocytes exhibited characteristics of newly generated cardiomyocytes, including single diploid nuclei and reduced cell size as compared to age-matched, sham-operated adult mouse myocytes. Notably, those smaller cardiomyocytes frequently resided alongside one another, consistent with local stimulation of cellular proliferation. Collectively, our data demonstrate that adult cardiomyocyte proliferation can be locally stimulated by an acute increase or decrease of ventricular pressure, and this mode of stimulation can be harnessed to promote cardiac repair.

  View details for DOI 10.1016/j.yjmcc.2019.06.006

  View details for PubMedID 31220468

• Topical Application Of A Mast Cell Stabilizer Improves Impaired Diabetic Wound Healing. J Invest Dermatol. Tellechea*, A., Bai*, S., Dangwal*, S., Theocharidis, G., et al 2019

  View details for DOI 10.1016/j.jid.2019.08.449

• Noncoding RNAs in Heart Failure HEART FAILURE Dangwal, S., Schimmel, K., Foinquinos, A., Xiao, K., Thum, T., Bauersachs, J., Butler, J., Sandner, P. 2017; 243: 423?45

  Abstract

  Heart failure is a major contributor to the healthcare burden and mortality worldwide. Current treatment strategies are able to slow down the transition of healthy heart into the failing one; nevertheless better understanding of the complex genetic regulation of maladaptive remodeling in the failing heart is essential for new drug discovery. Noncoding RNAs are key epigenetic regulators of cardiac gene expression and thus significantly influence cardiac homeostasis and functions.In this chapter we will discuss characteristics of noncoding RNAs, especially miRNAs, long noncoding RNAs, and circular RNAs, and review recent evidences proving their profound involvement during different stages of heart failure progression. Several open questions still prevent the extensive use of noncoding RNA-modulating therapies in clinics; yet they are becoming an attractive target to define novel regulatory mechanisms in the heart. In-depth study of their interaction with gene networks will refine our current view of heart failure and revolutionize the drug development in coming years.

  View details for DOI 10.1007/164_2016_99

  View details for Web of Science ID 000456448800020

  View details for PubMedID 27995387

• Impairment of Wound Healing in Patients With Type 2 Diabetes Mellitus Influences Circulating MicroRNA Patterns via Inflammatory Cytokines. ATVB Dangwal, S., et al 2015

  View details for DOI 10.1161/ATVBAHA.114.305048

• Thrombin Receptor Protease-Activated Receptor 4 Is a Key Regulator of Exaggerated Intimal Thickening in Diabetes Mellitus CIRCULATION Pavic, G., Grandoch, M., Dangwal, S., Jobi, K., Rauch, B. H., Doller, A., Oberhuber, A., Akhyari, P., Schroer, K., Fischer, J. W., Fender, A. C. 2014; 130 (19): 1700-+

  Abstract

  Diabetes mellitus predisposes to thrombotic and proliferative vascular remodeling, to which thrombin contributes via activation of protease-activated receptor (PAR) 1. However, the use of PAR-1 inhibitors to suppress remodeling may be limited by severe bleeding. We recently reported upregulation of an additional thrombin receptor, PAR-4, in human vascular smooth muscle cells exposed to high glucose and have now examined PAR-4 as a novel mediator linking hyperglycemia, hypercoagulation, and vascular remodeling in diabetes mellitus.PAR-4 expression was increased in carotid atherectomies and saphenous vein specimens from diabetic versus nondiabetic patients and in aorta and carotid arteries from streptozotocin-diabetic versus nondiabetic C57BL/6 mice. Vascular PAR-1 mRNA was not increased in diabetic mice. Ligated carotid arteries from diabetic mice developed more extensive neointimal hyperplasia and showed greater proliferation than arteries from nondiabetic mice. The augmented remodeling response was absent in diabetic mice deficient in PAR-4. At the cellular level, PAR-4 expression was controlled via the mRNA stabilizing actions of human antigen R, which accounted for the stimulatory actions of high glucose, angiotensin II, and H2O2 on PAR-4 expression, whereas cicaprost via protein kinase A activation counteracted this effect.PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy. The development of PAR-4 inhibitors might serve to limit mainly proliferative processes in restenosis-prone diabetic patients, particularly those patients in whom severe bleeding attributed to selective PAR-1 blockade or complete thrombin inhibition must be avoided or those who do not require anticoagulation.

  View details for DOI 10.1161/CIRCULATIONAHA.113.007590

  View details for Web of Science ID 000344067000013

  View details for PubMedID 25239438

• Diabetes-Associated MicroRNAs in Pediatric Patients With Type 1 Diabetes Mellitus: A Cross-Sectional Cohort Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Osipova, J., Fischer, D., Dangwal, S., Volkmann, I., Widera, C., Schwarz, K., Lorenzen, J. M., Schreiver, C., Jacoby, U., Heimhalt, M., Thum, T., Haffner, D. 2014; 99 (9): E1661?E1665

  Abstract

  Circulating microRNAs (miRNAs/miRs) are used as novel biomarkers for diseases. miR-21, miR-126, and miR-210 are known to be deregulated in vivo or in vitro under diabetic conditions.The aim of this study was to investigate the circulating miR-21, miR-126, and miR-210 in plasma and urine from pediatric patients with type 1 diabetes and to link our findings to cardiovascular and diabetic nephropathy risk factors in children with type 1 diabetes.miR-21, miR-126, and miR-210 concentrations were measured with quantitative RT-PCR in plasma and urine samples from 68 pediatric patients with type 1 diabetes and 79 sex- and age-matched controls.The study consisted of clinical pediatric patients with type 1 diabetes.Inclusion criterion for patients was diagnosed type 1 diabetes. Exclusion criteria were febrile illness during the last 3 months; chronic inflammatory or rheumatic disease; hepatitis; HIV; glucocorticoid treatment; liver, renal, or cardiac failure; or hereditary dyslipidemia. Patients were age and sex matched to controls.Main outcome parameters were changes in miR-21, miR-126, and miR-210 concentration in plasma and urine from type 1 diabetic patients compared with corresponding controls.Circulating miRNA levels of miR-21 and miR-210 were significantly up-regulated in the plasma and urine of the type 1 diabetic patients. Urinary miR-126 levels in diabetic patients were significantly lower than in age- and gender-matched controls and negatively correlated between the patient's glycated hemoglobin mean and miR-126 concentration value. In contrast, circulating miR-126 levels in plasma were comparable in both cohorts. For urinary miR-21, we found by an adjusted receiver-operating characteristic-curve analysis with an area under the curve of 0.78.Type 1 diabetic pediatric patients revealed a significant deregulation of miR-21, miR-126, and miR-210 in plasma and urinary samples, which might indicate an early onset of diabetic-associated diseases.

  View details for DOI 10.1210/jc.2013-3868

  View details for Web of Science ID 000342341400009

  View details for PubMedID 24937532

• MicroRNAs in the Bile of Patients With Biliary Strictures After Liver Transplantation LIVER TRANSPLANTATION Lankisch, T. O., Voigtlaender, T., Manns, M. P., Holzmann, A., Dangwal, S., Thum, T. 2014; 20 (6): 673?78

  Abstract

  Biliary complications after liver transplantation remain a major cause of morbidity and reduced graft survival. Ischemic-type biliary lesions (ITBLs) are common and difficult to treat. The pathophysiology of ITBLs remains unclear, and diagnostic markers are still missing. The analysis of microRNA (miRNA) profiles is an evolving field in hepatology. Our aim was to identify specific miRNA patterns in the bile of patients with ITBLs after liver transplantation. Liver transplant patients with biliary complications were included in a cross-sectional study. Patients with ITBLs (n?=?37), anastomotic strictures (ASs; n?=?39), and bile duct stones (BDSs; n?=?12) were compared. Patients with ITBLs were categorized by disease severity. The miRNA concentrations in bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation. The concentrations of microRNA 517a (miR-517a), miR-892a, and miR-106a* in bile were increased for patients with ITBLs versus patients with ASs or BDSs (P??0.05). miR-210, miR-337-5p, miR-577, and miR-329 displayed no statistical differences. In conclusion, miR-517a, miR-892a, and miR-106a* are increased in the bile fluid of patients with ITBLs versus patients with ASs or BDSs. An analysis of miRNA profiles may be useful in the diagnosis and management of patients with ITBLs. Future studies are needed to prove the potential prognostic value of these miRNAs.

  View details for DOI 10.1002/lt.23872

  View details for Web of Science ID 000340191200007

  View details for PubMedID 24648209

• Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy JOURNAL OF CLINICAL INVESTIGATION Bang, C., Batkai, S., Dangwal, S., Gupta, S., Foinquinos, A., Holzmann, A., Just, A., Remke, J., Zimmer, K., Zeug, A., Ponimaskin, E., Schmiedl, A., Yin, X., Mayr, M., Halder, R., Fischer, A., Engelhardt, S., Wei, Y., Schober, A., Fiedler, J., Thum, T. 2014; 124 (5): 2136?46

  Abstract

  In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrine-acting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.

  View details for DOI 10.1172/JCI70577

  View details for Web of Science ID 000335424500028

  View details for PubMedID 24743145

  View details for PubMedCentralID PMC4001534

• microRNA Therapeutics in Cardiovascular Disease Models ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54 Dangwal, S., Thum, T., Insel, P. A. 2014; 54: 185?203

  Abstract

  Cardiovascular diseases are a major cause of human morbidity and mortality, posing a high socioeconomic burden on the health sector worldwide. microRNAs (miRNAs) constitute a new class of unique molecular regulators involved in the pathophysiology of a wide range of disorders. Studies in the past decade have identified miRNA signatures of various cardiovascular disorders and successfully validated miRNA-based therapeutic options in various small and a few large experimental cardiovascular disease models. In these models, researchers manipulate the expression of miRNAs and downstream signaling cascades, aiming to prevent and cure cardiovascular disease. Here, we review and discuss the recent reports on the in vivo use of miRNA animal models and miRNA therapeutic development as well as provide an outlook for clinical applications in the near future.

  View details for DOI 10.1146/annurev-pharmtox-011613-135957

  View details for Web of Science ID 000329822200010

  View details for PubMedID 24111539

• MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses CIRCULATION RESEARCH Volkmann, I., Kumarswamy, R., Pfaff, N., Fiedler, J., Dangwal, S., Holzmann, A., Batkai, S., Geffers, R., Lother, A., Hein, L., Thum, T. 2013; 113 (8): 997?1003

  Abstract

  Transforming growth factor (TGF)-? was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known.To study the role of microRNAs in TGF-?-mediated angiogenic activity.MicroRNA profiling after TGF-? treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-?-treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-?, suggesting that derepression of MeCP2 after TGF-? treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-? effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells identified several deregulated genes important for endothelial cell function including sirtuin1 (Sirt1). In vivo experiments using endothelial cell-specific MeCP2 null or Sirt1 transgenic mice confirmed the involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Additional experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1.TGF-? impairs endothelial angiogenic responses partly by downregulating miR-30a-3p and subsequent derepression of MeCP2-mediated epigenetic silencing of Sirt1.

  View details for DOI 10.1161/CIRCRESAHA.113.301702

  View details for Web of Science ID 000329480200012

  View details for PubMedID 23960241

• Circulating miR-423_5p fails as a biomarker for systemic ventricular function in adults after atrial repair for transposition of the great arteries INTERNATIONAL JOURNAL OF CARDIOLOGY Tutarel, O., Dangwal, S., Bretthauer, J., Westhoff-Bleck, M., Roentgen, P., Anker, S. D., Bauersachs, J., Thum, T. 2013; 167 (1): 63?66

  Abstract

  Recently, the microRNA miR-423_5p was identified as a biomarker for left ventricular heart failure. Its role in patients with a systemic right ventricle and reduced ejection fraction after atrial repair for transposition of the great arteries has not been evaluated.In 41 patients and 10 age- and sex-matched healthy controls circulating miR-423_5p concentration was measured and correlated to clinical parameters, cardiac functional parameters assessed by magnetic resonance imaging, and cardiopulmonary exercise testing.Levels of circulating miR-423_5p showed no difference between patients and controls. Further, there was no correlation between miR-423_5p and parameters of cardiopulmonary exercise testing or imaging findings.In patients with a systemic right ventricle and reduced ejection fraction miR-423_5p levels are not elevated. Therefore, circulating miR-423_5p is not a useful biomarker for heart failure in this patient group.

  View details for DOI 10.1016/j.ijcard.2011.11.082

  View details for Web of Science ID 000320603100020

  View details for PubMedID 22188991

• The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy NATURE COMMUNICATIONS Ucar, A., Gupta, S. K., Fiedler, J., Erikci, E., Kardasinski, M., Batkai, S., Dangwal, S., Kumarswamy, R., Bang, C., Holzmann, A., Remke, J., Caprio, M., Jentzsch, C., Engelhardt, S., Geisendorf, S., Glas, C., Hofmann, T. G., Nessling, M., Richter, K., Schiffer, M., Carrier, L., Napp, L., Bauersachs, J., Chowdhury, K., Thum, T. 2012; 3: 1078

  Abstract

  Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload-induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

  View details for DOI 10.1038/ncomms2090

  View details for Web of Science ID 000309338100045

  View details for PubMedID 23011132

  View details for PubMedCentralID PMC3657998

• MicroRNAs in diabetes and diabetes-associated complications RNA BIOLOGY Lorenzen, J. M., Kumarswamy, R., Dangwal, S., Thum, T. 2012; 9 (6): 820?27

  Abstract

  Diabetes mellitus due to its high prevalence and associated complications is a major socioeconomic health problem. Diabetes is characterized by multiple macro- and microvascular complications (e.g. diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy). Research efforts aim to elucidate pathophysiological mechanisms contributing to the disease process. MicroRNAs are endogenous small single stranded molecules regulating targets through mRNA cleavage or translational inhibition. MicroRNAs regulate many biological cellular functions and are often deregulated during diseases. The aim of the present article is to summarize the current knowledge of the impact of microRNAs on the development of diabetes and its associated complications including endothelial and vascular smooth muscle cell dysfunction, diabetic cardiomyopathy, diabetic nephropathy, regulation of pancreatic beta cell function as well as skeletal muscle and hepatic involvement.

  View details for DOI 10.4161/rna.20162

  View details for Web of Science ID 000307077500012

  View details for PubMedID 22664916

• Transforming Growth Factor-beta-Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21 ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Kumarswamy, R., Volkmann, I., Jazbutyte, V., Dangwal, S., Park, D., Thum, T. 2012; 32 (2): 361?U441

  Abstract

  MicroRNAs are a class of small ribonucleotides regulating gene/protein targets by transcript degradation or translational inhibition. Transforming growth factor-? (TGF-?) is involved in cardiac fibrosis partly by stimulation of endothelial-to-mesenchymal transition (EndMT). Here, we investigated whether microRNA (miR)-21, a microRNA enriched in fibroblasts and involved in general fibrosis, has a role in cardiac EndMT.TGF-? treatment of endothelial cells significantly increased miR-21 expression and induced EndMT characterized by suppression of endothelial and increase of fibroblast markers. Overexpression of miR-21 alone also stimulated EndMT. Importantly, miR-21 blockade by transfection of specific microRNA inhibitors partly prevented TGF-?-induced EndMT. Mechanistically, miR-21 silenced phosphatase and tensin homolog in endothelial cells, resulting in activation of the Akt-pathway. Akt inhibition partly restored TGF-?-mediated loss of endothelial markers during EndMT. In vivo, pressure overload of the left ventricle led to increased expression of miR-21 in sorted cardiac endothelial cells, which displayed molecular and phenotypic signs of EndMT. This was attenuated by treatment of mice subjected to left ventricular pressure overload with an antagomir against miR-21.TGF-?-mediated EndMT is regulated at least in part by miR-21 via the phosphatase and tensin homolog/Akt pathway. In vivo, antifibrotic effects of miR-21 antagonism are partly mediated by blocking EndMT under stress conditions.

  View details for DOI 10.1161/ATVBAHA.111.234286

  View details for Web of Science ID 000299321200028

  View details for PubMedID 22095988

• Redox regulation of human protease-activated receptor-2 by activated factor X FREE RADICAL BIOLOGY AND MEDICINE Jobi, K., Rauch, B. H., Dangwal, S., Freidel, K., Doller, A., Eberhardt, W., Fischer, J. W., Schroer, K., Rosenkranz, A. C. 2011; 51 (9): 1758?64

  Abstract

  Activated factor X (FXa) exerts coagulation-independent actions such as proliferation of vascular smooth muscle cells (SMCs) through the protease-activated receptors PAR-1 and PAR-2. Both receptors are upregulated upon vascular injury but the underlying mechanisms have not been defined. We examined if FXa regulates PAR-1 and PAR-2 in human vascular SMCs. FXa increased PAR-2 mRNA, protein, and cell-surface expression and augmented PAR-2-mediated mitogenesis. PAR-1 was not influenced. The regulatory action of FXa on PAR-2 was concentration-dependent and mimicked by a PAR-2-selective activating peptide. PAR-2 regulation was not influenced by the thrombin inhibitor argatroban or PAR-1 siRNA. FXa increased dichlorofluorescein diacetate fluorescence and 8-isoprostane formation and induced expression of the NADPH oxidase subunit NOX-1. NOX-1 siRNA prevented FXa-stimulated PAR-2 regulation, as did ebselen and cell-permeative and impermeative forms of catalase. Exogenous H(2)O(2) increased PAR-2 expression and mitogenic activity. FXa promoted nuclear translocation and PAR-2/DNA binding of nuclear factor ?B (NF-?B); NF-?B inhibition prevented PAR-2 regulation by FXa. FXa also promoted PAR-2 mRNA stabilization through increased human antigen R (HuR)/PAR-2 mRNA binding and cytoplasmic shuttling. HuR siRNA abolished FXa-stimulated PAR-2 expression. Thus FXa induces functional expression of PAR-2 but not of PAR-1 in human SMCs, independent of thrombin formation, via a mechanism involving NOX-1-containing NADPH oxidase, H(2)O(2), NF-?B, and HuR.

  View details for DOI 10.1016/j.freeradbiomed.2011.08.003

  View details for Web of Science ID 000295954600014

  View details for PubMedID 21871560

• High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Dangwal, S., Rauch, B. H., Gensch, T., Dai, L., Bretschneider, E., Vogelaar, C., Schroer, K., Rosenkranz, A. C. 2011; 31 (3): 624?33

  Abstract

  Diabetes is associated with vascular remodeling and increased thrombin generation. Thrombin promotes vascular smooth muscle cell (SMC) mitogenesis and migration via protease-activated receptors (PAR)-1, PAR-3, and PAR-4. We investigated the effect of high glucose on expression and function of vascular thrombin receptors.In human vascular SMCs, high glucose (25 versus 5.5 mmol/L) induced a rapid and sustained increase in PAR-4 mRNA, protein, and cell surface expression. PAR-1 and PAR-3 expression were not changed. High glucose pretreatment (48 hours) enhanced thrombin or PAR-4-activating peptide but not PAR-1-activating peptide evoked intracellular calcium mobilization, migration, and tumor necrosis factor ? gene expression. This enhancement of thrombin-stimulated migration and gene expression by high glucose was abolished by endogenous PAR-4 knockdown. PAR-4 regulation was prevented by inhibition of protein kinase (PK)C-? and -? isoforms or nuclear factor (NF)?B. Nuclear translocation of NF?B in high glucose-stimulated SMCs led to PKC-dependent NF?B binding to the PAR-4 promoter in a chromatin immunoprecipitation assay. Furthermore, in situ hybridization and immunohistochemistry confirmed high abundance of PAR-4 in human diabetic vessels as compared with nondiabetic vessels.High glucose enhances SMC responsiveness to thrombin through transcriptional upregulation of PAR-4, mediated via PKC-?, -?, and NF?B. This may play an important role in the vascular complications of diabetes.

  View details for DOI 10.1161/ATVBAHA.110.219105

  View details for Web of Science ID 000287409900023

  View details for PubMedID 21164077