Bio

Honors & Awards


  • Myocardial Biology T32, NIH (2011-Present)
  • Predoctoral Fellowship, American Heart Association (2008-2010)

Professional Education


  • Doctor of Philosophy, University of Rochester (2011)

Stanford Advisors


Publications

Journal Articles


  • Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus PLOS GENETICS Miller, C. L., Anderson, D. R., Kundu, R. K., Raiesdana, A., Nuernberg, S. T., Diaz, R., Cheng, K., Leeper, N. J., Chen, C., Chang, I., Schadt, E. E., Hsiung, C. A., Assimes, T. L., Quertermous, T. 2013; 9 (7)

    Abstract

    Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.

    View details for DOI 10.1371/journal.pgen.1003652

    View details for Web of Science ID 000322321100049

    View details for PubMedID 23874238

  • Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart BASIC RESEARCH IN CARDIOLOGY Miller, C. L., Cai, Y., Oikawa, M., Thomas, T., Dostmann, W. R., Zaccolo, M., Fujiwara, K., Yan, C. 2011; 106 (6): 1023-1039

    Abstract

    Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca(2+)/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-? in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-?-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

    View details for DOI 10.1007/s00395-011-0228-2

    View details for Web of Science ID 000297708200009

    View details for PubMedID 22012077

  • Cyclic Nucleotide Phosphodiesterase 1 Regulates Lysosome-Dependent Type I Collagen Protein Degradation in Vascular Smooth Muscle Cells ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Cai, Y., Miller, C. L., Nagel, D. J., Jeon, K., Lim, S., Gao, P., Knight, P. A., Yan, C. 2011; 31 (3): 616-U299

    Abstract

    The phenotypic modulation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype is vital during pathological vascular remodeling and the development of various vascular diseases. An increase in type I collagen (collagen I) has been implicated in synthetic VSMCs, and cyclic nucleotide signaling is critical in collagen I regulation. Herein, we investigate the role and underlying mechanism of cyclic nucleotide phosphodiesterase 1 (PDE1) in regulating collagen I in synthetic VSMCs.The PDE1 inhibitor IC86340 significantly reduced collagen I in human saphenous vein explants undergoing spontaneous remodeling via ex vivo culture. In synthetic VSMCs, high basal levels of intracellular and extracellular collagen I protein were markedly decreased by IC86340. This attenuation was due to diminished protein but not mRNA. Inhibition of lysosome function abolished the effect of IC86340 on collagen I protein expression. PDE1C but not PDE1A is the major isoform responsible for mediating the effects of IC86340. Bicarbonate-sensitive soluble adenylyl cyclase/cAMP signaling was modulated by PDE1C, which is critical in collagen I degradation in VSMCs.These data demonstrate that PDE1C regulates soluble adenylyl cyclase/cAMP signaling and lysosome-mediated collagen I protein degradation, and they suggest that PDE1C plays a critical role in regulating collagen homeostasis during pathological vascular remodeling.

    View details for DOI 10.1161/ATVBAHA.110.212621

    View details for Web of Science ID 000287409900022

    View details for PubMedID 21148428

  • Ca2+/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells FEBS JOURNAL Jeon, K., Jono, H., Miller, C. L., Cai, Y., Lim, S., Liu, X., Gao, P., Abe, J., Li, J., Yan, C. 2010; 277 (24): 5026-5039

    Abstract

    The phenotypic change of vascular smooth muscle cells (VSMCs), from a 'contractile' phenotype to a 'synthetic' phenotype, is crucial for pathogenic vascular remodeling in vascular diseases such as atherosclerosis and restenosis. Ca(2+)/calmodulin-stimulated phosphodiesterase 1 (PDE1) isozymes, including PDE1A and PDE1C, play integral roles in regulating the proliferation of synthetic VSMCs. However, the underlying molecular mechanism(s) remain unknown. In this study, we explore the role and mechanism of PDE1 isoforms in regulating ?-catenin/T-cell factor (TCF) signaling in VSMCs, a pathway important for vascular remodeling through promoting VSMC growth and survival. We found that inhibition of PDE1 activity markedly attenuated ?-catenin/TCF signaling by downregulating ?-catenin protein. The effect of PDE1 inhibition on ?-catenin protein reduction is exerted via promoting glycogen synthase kinase 3 (GSK3)? activation, ?-catenin phosphorylation and subsequent ?-catenin protein degradation. Moreover, PDE1 inhibition specifically upregulated phosphatase protein phosphatase 2A (PP2A) B56? subunit gene expression, which is responsible for the effects of PDE1 inhibition on GSK3? and ?-catenin/TCF signaling. Furthermore, the effect of PDE1 inhibition on ?-catenin was specifically mediated by PDE1A but not PDE1C isozyme. Interestingly, in synthetic VSMCs, PP2A B56?, phospho-GSK3? and phospho-?-catenin were all found in the nucleus, suggesting that PDE1A regulates nuclear ?-catenin protein stability through the nuclear PP2A-GSK3?-?-catenin signaling axis. Taken together, these findings provide direct evidence for the first time that PP2A B56? is a critical mediator for PDE1A in the regulation of ?-catenin signaling in proliferating VSMCs.

    View details for DOI 10.1111/j.1742-4658.2010.07908.x

    View details for Web of Science ID 000284892300006

    View details for PubMedID 21078118

  • Targeting Cyclic Nucleotide Phosphodiesterase in the Heart: Therapeutic Implications JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Miller, C. L., Yan, C. 2010; 3 (5): 507-515

    Abstract

    The second messengers, cAMP and cGMP, regulate a number of physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression and cardiac structural remodeling. Emerging evidence suggests that multiple spatiotemporally distinct pools of cyclic nucleotides can discriminate specific cellular functions from a given cyclic nucleotide-mediated signal. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic AMP and/or cyclic GMP, control the amplitude, duration, and compartmentation of cyclic nucleotide signaling. To date, more than 60 different isoforms have been described and grouped into 11 broad families (PDE1-PDE11) based on differences in their structure, kinetic and regulatory properties, as well as sensitivity to chemical inhibitors. In the heart, PDE isozymes from at least six families have been investigated. Studies using selective PDE inhibitors and/or genetically manipulated animals have demonstrated that individual PDE isozymes play distinct roles in the heart by regulating unique cyclic nucleotide signaling microdomains. Alterations of PDE activity and/or expression have also been observed in various cardiac disease models, which may contribute to disease progression. Several family-selective PDE inhibitors have been used clinically or pre-clinically for the treatment of cardiac or vascular-related diseases. In this review, we will highlight both recent advances and discrepancies relevant to cardiovascular PDE expression, pathophysiological function, and regulation. In particular, we will emphasize how these properties influence current and future development of PDE inhibitors for the treatment of pathological cardiac remodeling and dysfunction.

    View details for DOI 10.1007/s12265-010-9203-9

    View details for Web of Science ID 000284694700011

    View details for PubMedID 20632220

  • Role of Ca2+/Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase 1 in Mediating Cardiomyocyte Hypertrophy CIRCULATION RESEARCH Miller, C. L., Oikawa, M., Cai, Y., Wojtovich, A. P., Nagel, D. J., Xu, X., Xu, H., Florio, V., Rybalkin, S. D., Beavo, J. A., Chen, Y., Li, J., Blaxall, B. C., Abe, J., Yan, C. 2009; 105 (10): 956-U59

    Abstract

    Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca(2+)/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca(2+)/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown.Herein, we investigate the role of Ca(2+)/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo.Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Furthermore, PDE1A plays a critical role in phenylephrine-induced reduction of intracellular cGMP- and cGMP-dependent protein kinase (PKG) activity and thereby cardiomyocyte hypertrophy in vitro.These results elucidate a novel role for Ca(2+)/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca(2+) and cGMP signaling cross-talk during cardiac hypertrophy.

    View details for DOI 10.1161/CIRCRESAHA.109.198515

    View details for Web of Science ID 000271505400004

    View details for PubMedID 19797176

  • Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart CIRCULATION RESEARCH Yan, C., Miller, C. L., Abe, J. 2007; 100 (4): 489-501

    Abstract

    Growing evidence suggests that multiple spatially, temporally, and functionally distinct pools of cyclic nucleotides exist and regulate cardiac performance, from acute myocardial contractility to chronic gene expression and cardiac structural remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cyclic GMP, regulate the amplitude, duration, and compartmentation of cyclic nucleotide-mediated signaling. In particular, PDE3 enzymes play a major role in regulating cAMP metabolism in the cardiovascular system. PDE3 inhibitors, by raising cAMP content, have acute inotropic and vasodilatory effects in treating congestive heart failure but have increased mortality in long-term therapy. PDE3A expression is downregulated in human and animal failing hearts. In vitro, inhibition of PDE3A function is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of antiapoptotic molecule Bcl-2 expression. Sustained induction of ICER may also cause the change of other protein expression implicated in human and animal failing hearts. These data suggest that the downregulation of PDE3A observed in failing hearts may play a causative role in the progression of heart failure, in part, by inducing ICER and promoting cardiac myocyte dysfunction. Hence, strategies that maintain PDE3A function may represent an attractive approach to circumvent myocyte apoptosis and cardiac dysfunction.

    View details for DOI 10.1161/01.RES.0000258451.44949.d7

    View details for Web of Science ID 000244571600008

    View details for PubMedID 17332439

  • Collateral sprouting of human epidermal nerve fibers following intracutaneous axotomy JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM Hahn, K., Sirdofsky, M., Brown, A., Ebenezer, G., Hauer, P., Miller, C., Polydefkis, M. 2006; 11 (2): 142-147

    Abstract

    Despite the clinical need, there are no therapeutic compounds available to promote peripheral nerve regeneration. In part, this may be due to a lack of sensitive measures of nerve growth. Here, we describe a novel approach of measuring collateral sprouting of epidermal nerve fibers (ENF) in human subjects and describe the effect of the neuroimmunophilin ligand timcodar dimesylate on collateral nerve sprouting. The objective of this study was to describe a model of intracutaneous axotomy and evaluate the ability of timcodar dimesylate to accelerate human cutaneous nerve regeneration through collateral sprouting. Subjects were randomized to receive placebo, 12.5 or 50 mg/day timcodar dimesylate in a prospective, two-center, double-blind, placebo-controlled trial. A 3-mm distal thigh punch skin biopsy was performed at baseline, and a 4-mm overlapping concentric biopsy was taken after 56 days of treatment. Biopsies were processed to visualize ENF, and the collateral sprouting distance (CSD) was measured. Sixty-two subjects completed the trial, and the CSD was measurable in 52. The CSD (mean +/- SEM) was 474.5 microm +/- 38.3, 473.4 microm +/- 28.4, and 450.8 microm +/- 26.5 for the placebo, low and high dose groups, respectively (p = 0.84). The baseline ENF density was associated with the CSD (p = 0.02). Collateral sprouting was efficiently measured using an intracutaneous axotomy model and suggests a collateral sprouting rate of 8.5 microm/day in healthy subjects. The model was consistent across treatment groups and had a low coefficient of variation. Timcodar dimesylate treatment was safe over an 8-week period but did not improve collateral sprouting among healthy subjects.

    View details for Web of Science ID 000238289900006

    View details for PubMedID 16787512

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