Professor of PharmacologyOur research 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. Patholgoical 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 assoicated 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 antiapoptotic 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.
Purdom S, Sheveleva E, Sun HP and Chen QM (2007) Translational Control of Nrf2 Protein in Activation of Antioxidant Response Element by Oxidants. Mol. Pharm., 72: 1074-1081 (within top 10 most downloaded/ viewed article Aug, 2007).
Xu W, Chou C-L, Sun HP, Fujino H, Chen QM and Regan JW (2008)FP Prostanoid Receptor Mediated Induction of the Expression of Early Growth Response Factor-1 by Activation of a Ras/Raf/MAPK Signaling Cascade. Mol. Pharm., 73: 111-118
Sun, HP and Chen QM (2008) GSK3 Regulates Corticosteroid Induced COX-1 Gene Expression in Cardiomyocytes. Cardiovasc. Tox., 8(2): 93-100
Sun, HP, Sheveleva E. and Chen QM (2008) Corticosteroids Induce Cyclooxygenase 1 Expression in Cardiomyocytes: Role of Glucocorticoid Receptor and Sp3 Transcription Factor. Mol. Endocrinol., in press. doi:10.1210/me.2007-0302
Pysher MD, Chen QM and Vaillancourt RR (2008) Arsenic Alters Vascular Smooth Muscle Cell Focal Adhesion Complexes Leading to Chronic Stimulation of FAK-SRC Mediated Pathways. Tox. Appl. Pharm., in press. doi:10.1016/j.taap.2008.04.002
Xie LF, Xu BB, Pandey R, Tsaprailis GT and Chen QM (2008) Genomic and Proteomic Profiles of Oxidative Stress in Human Diploid Fibroblasts. Biogerontology, in press. doi:10.1007/s10522-008-9157-3
Sun HP, Xu BB and Chen QM (2008) LY294002 Inhibits Glucocorticoid-induced COX-2 Induction in Cardiomyocytes through a Phosphatidylinositol 3 Kinase Independent Mechanism. Tox. Appl. Pharm., in press. doi:10.1016/j.taap.2008.05.024
Sun H, Sheveleva E, Xu BB, Inoue H, Bowden GT and Chen QM (2008) Corticosteroids Induced COX-2 Expression in Cardiomyocytes: Role of Glucocorticoid Receptor and c/EBP�Am. J. Physiol. Cell Physiol. in press. doi:10.1152/ajpcell.90646.2007
Sun HP, Xu BB, Inoue H and Chen QM (2008) p38 MAPK Mediates COX-2 Gene Expression by Corticosterone in Cardiomyocytes. Cell Signaling, in press. doi:10.1016/j.cellsig.2008.07.003
Chondrogianni N, Trougakos IP, Kletsas D, Chen QM and Gonos ES (2008) Partial Proteasome Inhibition in Human Fibroblasts Triggers Accelerated M1 Senescence or M2 Crisis Depending on the p53 and Rb Status in Human Fibroblasts.
Aging Cell, in press. doi: 10.1111/j.1474-9726.2008.00425.x
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