Phone: (914) 594-3121
Department of Pharmacology
New York Medical College, BSB Rm. 509
15 Dana Road
Valhalla, NY 10595
Research Interest and Historical View:
1- Immediately after receiving my Ph.D. degree, my postdoctoral fellowship at the Rockefeller University focused on the purification of a human liver protein (heme oxygenase, HO-1) and its gene sequence, including the promoter region. Thereafter, I led a productive research that further characterized the biochemistry of heme oxygenase and the implication of its activity to heme and iron homeostasis and the function of hematopoietic stem cells. The examination of the biological function of CO led to the discovery of the role of heme arginine in lowering blood pressure as a result of the cross-talk between CO and NO which resulted in the development of a patent (1988 before the discovery of NO signaling) for arginine, an amino acid effective in lowering blood pressure in the rodent and in man. The patent royalties supported my institution and my research. This discovery was based on the seminal observation and led to the landmark discovery that induction of HO-1 with SnCl2 prevents the development of hypertension (Science 1989). This landmark publication was the first to place HO-1 in the realm of cardiovascular disease/research. My current research program focuses on understanding the cellular and molecular mechanisms of HO-1 cytoprotective actions and developing therapeutic strategies for treatment of cardiovascular and metabolic diseases.
2- HO-1/EET and Metabolic Syndrome/Diabetes. EET/HO acts as a molecular “switch” to genetically reprogram adipocyte stem cells and, subsequently, vascular endothelium through activation of a unique signaling cascade that results in the amplification of protective circuits and provides resistance to vascular dysfunction. Increased HO-1 expression provides protection for stem cell function and decreases adiposity. HO-1 also serves as the mediator of cross-talk between adipose tissue and the vasculature. Our studies demonstrated that HO-1 expression in epicardial tissue provides protection to heart function and attenuates myocardial infarction (MI) and heart failure. Both human and animal models of diabetes and obesity were utilized to examine the use of stem cell intervention and gene therapy to amplify HO-1 levels. Additionally, our research approach proved to be a powerful tool in the identification of novel biomarkers for cardiovascular and metabolic disease (e.g. circulating endothelial cells and progenitor stem cells [EPCs] for better prognosis). We believe that the effect of anti-diabetic drugs alone, or in combination with antioxidant genes, have a differential impact on stem cell function and vascular disease. We showed an independent role of HO-1 and HO-2 in vascular protection and adiposity. For example, deletion of HO-2, increased obesity and decreased EET can be rescued by pharmacological upregulation of HO-1, signifying the role of both HO-1/-2 in adipocyte/vascular protection by regulating the EET-adiponectin-pAMPK signaling pathway.
3- The PGC-1α-EET-HO-1 regulatory axis. Obesity leads to metabolic syndrome and type 2 diabetes mellitus (DM2), which are associated with increased morbidity and mortality, predominantly as a result of cardiomyopathy and other cardiovascular complications. Increased fat mass is a systemic condition characterized by increased ROS and inhibition of anti-oxidant genes such as HO-1 and increased degradation of EETs. Pericardial fat along with dysfunctional adipocytes secrete inflammatory cytokines such as TNFα and reduce insulin sensitivity leading to cardiac dysfunction and fibrosis. Increased HO-1 expression and HO-1 activity is associated with an increase in adiponectin secretion that prevent differentiation and enlargement of adipocytes resulting in the stimulation of nitric oxide (NO) bioavailability and improved endothelial function and glucose tolerance. Oxidative stress is both a main cause and consequences of obesity and diabetes which eventually leads to the diabetic phenotype. Mitochondrial biogenesis and oxidative metabolism are controlled by Peroxisome Proliferator-Activated Receptor gamma coactivator 1-alpha (PGC-1α), originally described as a coactivator of PPAR-γ that modulated thermogenesis. There is growing evidence that PGC-1α plays a role in disorders such as obesity, diabetes, and cardiomyopathy. EETs are synthesized from arachidonic acid by cytochrome P450 as autocrine and paracrine mediators. EETs exhibit potent biological effects including adipogenesis, vasodilatation and inhibition of the inflammatory response. EETs upregulate HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation, indicating the existence of a crosstalk between HO-1 and EETs. Caloric restriction (CR) regiment is an experimental regiment found to be cardio protective and to increase PGC-1 α levels. Our goal is to understand the role of PGC-1α in obesity, pericardial fat and its effect on cardiac metabolism and remodeling. To that end, we will study the antioxidant and anti-obesity properties of PGC-1 α through its interaction with HO-1. Finding ways to proceed safely is currently one of the major interests to effectively activate PGC-1α that may prove to be a powerful tool in reducing obesity-mediated cardiomyopathy and heart failure.