Overview

The major goals of the Department of Molecular Cardiology are:

• Continuation of the long-standing tradition at the Cleveland Clinic Foundation for research excellence in the area of cardiovascular biology.
• Development of cutting-edge research programs to address significant physiological and pathophysiological mechanisms that occur in the heart and in the vasculature.
• Maintenance of an active linkage between basic and clinical investigators with research program in cardiovascular biology.
• Provide educational opportunities for Students and Fellows to receive research training in cardiovascular biology.

To realize these goals, faculty members within the Department lead active research programs which deal with a broad range of cardiovascular problems. The types of analyses range from basic studies of protein structure, to the dissection of molecular and cellular mechanisms, to investigations conducted in animal models and in humans. Currently, the Department is composed of 19 staff members with appointments ranging from the Full Staff through the Project Scientist level. Research programs in the Department of Molecular Cardiology are organized into five major areas of interest: 1. Hypertension; 2. Heart Failure; 3. Thrombosis; 4. Vascular Biology; and 5. Structural Biology.

Research in the hypertension area seeks to continue the tradition of research excellence in this area established by Cleveland Clinic investigators, such as Irvine H. Page, Merlin Bumpus and Robert Tarrazi. Studies include the analyses of the structure and function of the angiotensin I-converting enzyme (ACE) which controls formation of the regulatory peptide angiotensin II (Dr. I. Sen). Angiotensin II is a focus of the research effort in the laboratory of Dr. Karnik who seeks to understand how this peptide regulates blood pressure by functioning as a ligand for specific receptors and the structural basis for recognition of this ligand by these receptors. The angiotensin receptors belong to the large family of seven transmembrane-spanning receptors. Dr. Perez’s laboratory is involved in the analysis of the basis for ligand recognition specificity and activation of the adrenergic members of this receptor family. Together, these investigators established a strong program to understand the biology of the seven transmembrane G-protein coupled receptors which regulate blood pressure. Several of the above mentioned faculty members are also utilizing transgenic animal approaches to compliment their molecular and cellular studies so that hypotheses can be generated and tested in vivo as well as in vitro.

A second major emphasis of research in the Department is heart failure. Heart failure has become a major health problem in the United States reaching epidemic proportions. To meet this challenge, three laboratories of senior investigators (Drs. S. Sen and Misono) have dedicated research efforts in this area. Dr. Sen’s laboratory seeks to identify the molecular players involved in the initiation and progression of heart failure and seeks to develop strategies to reverse the transition from hypertrophy to heart failure. Dr. Misono’s laboratory is involved in research to characterize atrial natritic factor and its receptor at a structural level. This ligand-receptor system is believed to play a central role in hypertension and the heart failure response.

Thrombosis remains the leading cause of death in the United States. A better understanding of the molecular mechanisms of thrombosis, hemostasis and fibrinolysis represent a third area of research which are emphasized within several laboratories in the Department of Molecular Cardiology. The laboratories of Drs. Plow and Hoover-Plow are interested in the function of the components of the plasminogen system, the molecular pathway which is responsible for the dissolution of blood clots and a system which also influences the migration of cells. Analyses in these laboratories utilize mice in which the genes for various components of the plasminogen system have been inactivated. These mice provide a means to dissect the role of the plasminogen system in physiologic and pathophysiologic events. Essential to the function of blood coagulation proteins is their post-translational modification by g-carboxylation. Dr. Berkner’s lab seeks to define the regulation of this event and to characterize the responsible g-carboxylase. The laboratories of Drs. Fox and Plow have major research efforts focused on the role of platelets in thrombus formation. The receptors that mediate platelet adhesion and aggregation, events that are central to thrombus formation, are under analyses. Dr. Byzova’s laboratory investigates the interface between the blood coagulation and platelet arms of the hemostatic system by analyzing how platelets control thrombin generation. The occurrence of thrombosis in humans is determined by specific risk factors. The laboratory of Dr. Hoover-Plow also seeks to determine why a specific lipoprotein, Lp(a), is an independent and major risk factor for cardiovascular diseases. Dr. Qing Wang conducts searches within large patient populations and families for genes that are associated with or are the causes of specific cardiac and vascular pathologies.

Vascular biology is the fourth area of emphasis in the Department of Molecular Cardiology and is broadly studied throughout the Lerner Research Institute. Cell adhesion, intracellular signaling events and pathways and regulation of the cytoskeleton represent specific cellular processes which contribute to complex physiologic and pathophysiologic responses such as angiogenesis, atherosclerosis and restenosis. Cell adhesion mechanisms are major areas of emphasis within the laboratories of Drs. Byzova, Fox and Plow. Studies of ligand binding to integrin adhesion receptors and activation of these adhesion receptors are major topics of investigation. Together, these laboratories seek to gain insights into the processes underlying atherosclerosis, restenosis, and therapies for these diseases down-stream signaling events and cytoskeletal linkages triggered by activation and occupancy of these receptors are areas of intense investigation.

The above synopsis of ongoing research activities within the Department of Molecular Cardiology indicates a heavy emphasis on peptide and protein functional analyses. To compliment this endeavor, Dr. Qin, a structural biologist, uses NMR spectroscopy to analyze the 3-dimensional structure of a wide variety of proteins. Together, with faculty members in various departments throughout the Lerner Research Institute, Dr. Qin leades a growing body of structural biologists within the Cleveland Structural Biology community, who seek to bring state-of-the-art approaches to provide high resolution understanding of how protein molecules work. Knowledge of the three-dimensional structure of proteins not only provide insights into their modus operandi but also is the future of drug design to target these problems.