Cardiovascular Pharmacology Faculty

DWilliam J. Lehman, Ph.D.avid Atkinson, Ph.D.
Professor of Physiology and Biophysics.
Research Interests: Dr. Atkinson’s research efforts aim to provide detailed structural and conformational information on the molecular organization and interactions of lipids and proteins in plasma lipoproteins. The primary approaches use the techniques of X-ray/neutron scattering, protein crystallography, structural electron microscopy/image processing, nuclear magnetic resonance, calorimetry, circular dichroism, and molecular modeling to probe the structure and physical properties of lipoproteins, lipoprotein apoproteins and lipid/apoprotein reassembled model systems.

Victoria M. Bolotina, Ph.D.
Professor of Medicine and Physiology.
Research Interests: The research focus is on ion channels and mechanisms of calcium signaling in a variety of cell types. Methodologies include patch clamp, high resolution confocal and deconvolution imaging, and molecular and biochemical techniques (including knock-out mouse models) to study single channels and whole-cell currents, regulation of membrane potential, intracellular calcium, vascular tone, and expression, activity and localization of several major determinants in calcium signaling cascades. The large part of her recent research is devoted to studying store-operated channels and capacitative calcium entry pathway in vascular smooth muscle cells, cardiac myocytes, platelets, T-lymphocytes, astrocytes and beta cells.

Richard A CohenRichard A. Cohen, M.D.
Professor of Medicine, Physiology and Pharmacology.
Research Interests: The research programs of the Vascular Biology Unit are directed towards an integrative molecular understanding of abnormal vascular endothelial and smooth muscle cell function in diseased blood vessels and its contribution to abnormal vascular reactivity, hypertrophy, inflammation, and atherogenesis. Research projects focus on the mechanisms by which vascular risk factors associated with diabetes mellitus, hypercholesterolemia, and hypertension lead to abnormal production of vasoactive factors from the endothelium and also how they alter the smooth muscle cell response. These factors include nitric oxide, prostanoids, oxygen–derived free radicals, cytokines, and growth factors. Experimental approaches employ cell physiology of cultured endothelial and smooth muscle cells with measurements of intracellular calcium and oxygen–derived free radicals, coupled with studies of molecular signaling. The influence of altered production of endothelial factors and signaling cascades on inflammatory responses and cell adhesion is studied as it applies to the development of atherosclerotic lesions, particularly in diabetes. Post-translational modification by tyrosine nitration and thiol oxidation of proteins studied by immuno/affinity labeling and mass spectrometry has been shown to alter the function of endothelial cell nitric oxide synthase, sarcoplasmic reticulum ATPase, endothelial nitric oxide synthase, p21ras, manganese superoxide dismutase, and prostacyclin synthase. S-glutathiolation has been demonstrated as a reversible thiol modification that that modulates cell signaling. Proteomic approaches are being used to screen proteins for oxidant modifications that occur as physiological mechanisms or are a consequence of excess reactive nitrogen species.

William J. Lehman, Ph.D.James A. Hamilton, Ph.D.
Professor of Physiology and Biophysics.
Research Interests: Dr. Hamilton’s laboratory is developing and applying novel physical approaches to study of obesity, metabolic syndrome, and cardiovascular disease. 13C NMR methods pioneered in his laboratory have been used to describe the interactions of fatty acids and drugs with binding sites on albumin, and new studies are currently correlating important details predicted by NMR with recent x-ray crystal structure. His laboratory has determined the complete solution structure of several intracellular fatty acid binding proteins (FABP) by multi-dimensional NMR and is studying the molecular details of ligand binding to FABP. New fluorescence approaches have been developed to characterize the diffusion of fatty acids into adipocytes and evaluate the effects of drugs and inhibitors on fatty acid uptake. A newer focus of research is on imaging methodologies, mainly magnetic resonance imaging (MRI), of fat tissue and atherosclerosis. These studies extend from animal model systems (mouse and rabbit) to humans. The work emphasizes interactions of different disciplines on translation of basic biophysics to human disease aspects.

Photo on 7-1-13 at 11 06 AMZhen Y. Jiang, M.D., Ph.D.
Associate Professor of Pharmacology and Medicine. Metabolic Syndrome, Obesity, Diabetes and Innate Immunity
Currently, my lab mainly focuses on understanding how insulin signaling networks and innate immunity regulate metabolic functions.

1. CDP138 and its signal networks related to glucose and lipid metabolisms. In collaboration with Dr. Marcus Krueger and Dr. Matthias Mann’s laboratory at the Planck Institute of Biochemistry in Munich, Germany, we applied a SILAC-based quantitative proteomics approach and identified multiple phosphoproteins from insulin-stimulated adipocytes. As a result, we found that CDP138, a novel phosphoprotein containing C2 domain, is involved in the regulation of GLUT4 translocation. We also produced CDP138 knockout mouse model. Currently, we are using TIRF microscopy-based live cell imaging, protein-protein interactions, gene expression profiling and the knockout mouse model to study the signal network of CDP138 and its role in the regulation of glucose and lipid metabolisms and neuronal functions.

2. Exploring the role of neutrophils and neutrophil elastase (NE) in the development of obesity-related adipose inflammation, insulin resistance and cardiovascular dysfunction. Using quantitative serum proteomic approach, we recently identified that there is an imbalance between NE and its inhibitor alpha-1-antitrypsin in both obese human subjects and mouse models. Interestingly, both NE knockout mice and human A1AT transgenic mice are resistant to high-fat diet-induced body weight gain, adipose inflammation, fatty liver and insulin resistance. We also observed that NE knockout mice have higher AMP kinase activity and fatty acid oxidation rate. Currently, we are exploring molecular and cellular mechanisms whereby obesity regulates neutrophils activity and subsequent adipose inflammation, fatty liver, insulin resistance and cardiovascular dysfunctions using approaches such as live animal imaging, bone marrow transplantation, transcriptional regulation and lipidomics with different mouse models.

Katya Ravid, Ph.D.,
Professor of Biochemistry and Medicine.
Research Interests: The cells of all blood lineages arise from pluripotent hematopoietic stem cells that reside in the marrow. The bone marrow also contains stem cells of other lineages, including fat, vascular etc. Our research is focused on two interrelated projects that bear on mechanisms associated with the development of blood and vascular pathologies: (1) Studies in the lab center on molecular mechanisms involved in cell cycle control during the development of bone marrow megakaryocytes into platelets, a process that includes cellular polyploidization prior to platelet fragmentation. We also identified mechanisms of polyploidy in vascular smooth muscle cells, and found that the degree of polyploidy serves as an excellent biomarker for aging; (2) Ongoing studies explore the role of vascular and bone marrow cell (progenitors and mature) adenosine receptors in vascular regeneration during injury or atherosclerosis. Transgenic and knockout mouse models are used to assist in exploring mechanisms in vivo.

Assistant Professor of Pharmacology and Medicine, Division of Cardiovascular Medicine
Our laboratory utilizes an integrated physiological, pharmacological, molecular, and gene-targeting approach to investigate the anti-hypertensive role(s) ofcentral, and more specifically hypothalamic paraventricular nucleus (PVN), Gαi2-subunit proteins in the endogenous GPCR-activated pathways that regulate central sympathetic outflow (with particular focus on the renal sympathetic nerves), fluid and electrolyte homeostasis, and systemic blood pressure regulation in salt-resistant and salt-sensitive animal models. These NIH funded studies, which encompass the fields of water and electrolyte homeostasis, CNS autonomic regulation, and high blood pressure research are designed to provide a detailed insight into the “anti-hypertensive” PVN evoked Gαi2-subunit protein mediated renal sympathetic signature acting to provide salt-resistance vs. salt-sensitivity in animal models. Via an integrated in-vivo translational approach our laboratory manipulates both whole brain, and specifically PVN, Gαi2-subunit protein levels to highlight the previously unknown role of PVN Gαi2-subunit proteins in countering the development of salt-sensitive hypertension. We believe our research strategy of establishing the mechanisms involved in preventinghypertension is very likely to result in the development of new pre-clinical diagnostic and therapeutic targets for the treatment of hypertension that have been overlooked in traditional pro-hypertensive orientated investigations. Collectively our research program is designed to enhance the current understanding and theoretical modeling of the brain GPCR mediated signaling mechanisms involved in salt-resistant vs salt-sensitive hypertension.

WalshKenneth Walsh, Ph.D.
Professor of Medicine and Director, Whitaker Cardiovascular Institute.
Research Interests: Research in the Walsh laboratory has been focused in three areas. The major project investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Many of these studies involve analyses of the PI3-kinase/Akt/GSK/Forkhead signaling axis. This pathway is of critical importance in the regulation of organ growth and body size. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). The second project investigates the role of the immune system in vascular disease. The formation of atherosclerotic lesions involves inflammatory cell interactions within the endothelium and subsequent extravasation into the vessel wall. Accelerated atherosclerosis is a critical factor contributing to the stroke and coronary heart disease that is a major cause of death among young women with systemic lupus erythematosus. The third project analyzes the actions of adiponectin on cardiovascular tissues. It is now recognized that adipose tissue functions as an endocrine organ and that obesity contributes to cardiovascular and metabolic disorders through an imbalance of cytokines. Adiponectin is an adipocyte-derived cytokine that is down-regulated in obese individuals. We have found that adiponectin has beneficial actions on the cardiovascular system by directly acting on the heart and blood vessels.

photo of Dr. WongJoyce Y. Wong, Ph.D.
Associate Professor of Biomedical Engineering.
Research Interests: Dr. Wong’s main research interest is in the development of new biomaterials that interact with living cells in novel ways. She is interested in questions relating to biocompatibility and control of cellular behavior at the cell-material interface for drug delivery and tissue engineering applications. Her approach includes direct measurement of physicochemical interactions between biological molecules and model biomembrane systems. Dr. Wong’s research uses a combination of approaches from materials science and engineering, polymer science and polymer physics, colloid and surface science, cell culture, and biophysics.