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MARLENE
RABINOVITCH, M.D. Clinical Activities and Research Interests: Our research focuses on the regulation of genes associated with vascular development and disease. We have shown that a novel smooth muscle cell elastase plays a pivotal role in the pathobiology of cardiovascular diseases including pulmonary hypertension, vein graft atherosclerosis, transplant arteriopathy and rejection, coronary artery disease, restenosis, myocardial ischemia and myocarditis. The mechanism is related to liberation of growth factors and cytokines, activation of matrix metalloproteinases, induction of tenascin-C, clustering of beta integrins and phosphorylation of growth factor receptors. Inhibition of elastase prevents or reverses the pathology in experimental animals. In vessels, this involves smooth muscle cell apoptosis and caspase medited degradation of the excess extracellular matrix. We are now pursuing fundamental studies which address the transcriptional regulation of elastase by AML1 and how this relates to genetic mechanisms of disease, focusing on polymorphisms in the serotonin transporter, mutations in a bone morphogenetic protein receptor, and overexpression of a caclium binding protein, Mts1. These studies use cultured cells, transgenic mice, gene arrays and gene therapy and are aimed at developing new treatments. In our studies related to regulation of cell motility, a key feature of vascular pathology, we identified the microtubule associated protein LC-3 as pivotal in the efficiency of mRNA translation of genes including fibronectin and apolipoprotein D. We determined that LC3 is regulated by nitric oxide, and are currently investigating how this leads to its phosphorylation and binding to mRNA. In addition, we are relating LC-3 to the migration of other cell types including neural crest cells which regulate cardiac development. We have also cloned a novel chymase which regulates the enhanced production of angiotensin II, endothelin 1, collagen and transforming growth factor beta. Since the transgenic mouse that overexpresses this gene is hypertensive, and since the spontaneously hypertensive rat also produces excess chymase, we are investigating whether an increase in the synthesis of the human chymase enzyme is responsible for a refractory form of systemic hypertension. A major program will be combined with that of Dr. Richard Bland in investigating the regulation, expression and function of genes that coordinate pulmonary alveolar and vascular development and how they are perturbed by prematurity and mechanical ventilation leading to chronic lung disease. Recent Publications: Jones PL, Jones FS, Zhou B and Rabinovitch M. (1999) Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type1 collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathyway and a 122-base pair promoter element. J Cell Sci; 112:435-445. Mason CAE. Bigras J-L, OBlenes SB, McIntyre B, Nakamura N, Kaneda Y, Rabinovitch M. (1999). Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin dependent neointimal formation. Nature Med 5: 176-188. Mason CAE, Chang, P, Fallery C, Rabinovitch M. (1999) Nitric oxide mediates LC-3-dependent regulation of fibronectin in ductus arteriosus intimal cushion formation. FASEB J, 13:1423-1434. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. (2000). Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nature Med 6: 698-702. Cowan KN, Jones PL, Rabinovitch M. (2000) Elastase and matrix metalloproteinase inhibitors induce regression and tenascin-C antisense prevents progression of vascular disease. J Clin Invest 2000,105:21-34. Mitani Y, Zaidi SHE, Dufourcq P, Thompson K, Rabinovitch M. (2000). Nitric oxide reduces vascular smooth muscle cell elastase activity through a cGMP mediated suppression of ERK phosphorylation and AML1B nuclear partitioning. FASEB J 14: 805-814 Zaidi SHE, You X-M, Ciura S, OÕBlenes S, Husain M, Rabinovitch M. (2000) Suppressed smooth muscle proliferation and inflammatory cell invasion following arterial injury in elafin-overexpressing mice. J Clin Invest, 105:1687-1695. Gou C, Ju H, Leung D, Massael H, Shi M, Rabinovitch M. (2001) A novel vascular smooth muscle chymase is upregulated in spontaneously hypertensive rats. J Clin Invest, 107: 703-15 Ju H, Gros R, You X, Tsang S, Husain M, Rabinovitch M. (2001). Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. PNAS 98: 7469-7474. Mitani Y, Zaidi SHE, Dufourcq P, Thompson K, Rabinovitch M. (2001) Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP-mediated suppression of ERK phosphorylation and AML1B nuclear partitioning. FASEB J. 2000,14:805-814. Zaidi SHE, You X, Ciura S, Husain M, Rabinovitch M. (2002). Overexpression of the serine elastase inhibitor elafin protects mice from hypoxic pulmonary hypertension. Circulation 105: 526-521. Education and Training: McGill University, B.Sc., 1967 McGill University, M.D., 1971 Intern in Pediatrics, University of Colorado Medical Center, Denver, CO, 1971-1972 Resident in Pediatrics, University of Colorado Medical Center, Denver, CO, 1972-1973 Clinical
Fellow in Pediatric Cardiology, Clinical
Fellow in Pediatric Cardiology, Research
Fellow in Pediatric Cardiology,
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