Our researach focuses on the molecular mechanisms of oxidative stress and pharmacological agents of cytoprotection. Oxidants are byproducts of aerobic metabolism. The level of oxidants increases as a result of radiation, intoxication of certain xenobiotics and disease states involving ischemic reperfusion or inflammatory response. Oxidative stress has been shown to contribute to aging, cancer and heart disease. Our research projects are: 1) Molecular Mechanisms of Oxidative Stress Response using human fibroblasts as an experimental model system. We characterize genes and proteins that are upregulated or altered by oxidants using genomic and proteomic approaches to identify critical molecules that control a series of cellular changes resulting from oxidant exposure such as premature senescence and apoptosis; 2) The Role of Oxidative Stress in Heart Failure. Pathological analyses often reveal apoptotic cardiomyocytes, hypertrophy of remaining cardiomyocyte, and fibrosis or hyperplasia of fibroblasts in failing hearts. We isolate cardiomyocytes and fibroblasts from the heart of experimental animals to determine the cellular and molecular changes that are produced by oxidants in these cell types.
Our studies indicate that oxidants can induce hypertrophy of cardiomyocytes in culture. Thorough analyses indicate a role of phosphatidylinositol 3 kinase, MAP kinases, AP-1 transcription factors, and cyclooxygenase-2 in oxidant-induced cardiomyocyte hypertrophy. In contrast to cardiomyocyte hypertrophy, fibrosis is a disease involving proliferation of fibroblasts and changes in the expression of extracellular matrix proteins and secreted proteases by fibroblasts. Genomic profiling, proteomic mining and transcription factor measurements are ongoing to determine the influence of cell type on molecular and cellular changes induced by oxidants and to search for critical targets that play a role in fibrosis or cardiomyocyte hypertrophy associated with oxidative stress.
An important emphasis of our laboratory is searching for pharmacological agents that serve as cytoprotectants. Recent studies have pointed to a role of apoptosis in heart failure associated with cardiomyopathy and myocardial infarction. Our laboratory has found that corticosteroids can prevent cardiomyocytes to undergo apoptosis in vitro. Genomic and proteomic analyses show elevation of certain antioxidant proteins and anti-apoptotic proteins induced by corticosteroid. Currently we are exploring the transcription factors regulating cell survival responses and validating our in vitro findings with in vivo experimental models of heart failure.
