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| Research |
| Wafic Said Molecular Cardiology & Gene Therapy Research Laboratory |
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This laboratory is dedicated to investigating basic mechanisms of cardiovascular disease and the use of gene therapy to develop new modalities of treatment. Substantial funding for the establishment of the laboratory was provided by Mr. Wafic Said, a prominent international businessman and philanthropist. Ongoing projects include:
Gene Transfer of Tissue Factor Pathway Inhibitor In this work, we examine the protective effect of tissue factor pathway inhibitor (TFPI) overexpressed locally at sites of vascular damage. We found that local gene transfer of TFPI is effective against thrombosis and restenosis in balloon-injured atherosclerotic arteries. In contrast to conventional treatments, however, local gene therapy is completely free of systemic bleeding risk. The ability of TFPI to regulate thrombosis, intimal hyperplasia, cell migration, atherosclerosis, and angiogenesis is studied in a large animal (pig) carotid balloon angioplasty model, an LDL receptor-deficient atherosclerotic rabbit model (the heritable hyperlipidemic Watanabe rabbit), and a model of human saphenous bypass grafting in cholesterol-fed rabbits. Recent Publications and Abstracts Related to this Project. Zoldhelyi, P., McNatt, J.M., Shelat, H.S.,Yamamoto, Y., Chen, Z.-Q., Willerson, J.T. Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human tissue factor pathway inhibitor. Zoldhelyi, P., Chen, Z.-Q., McNatt, J.M., Willerson, J.T. Gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries. Zoldhelyi, P., McNatt, J., Shelat, H.S., Chen, Z.-Q., Willerson, J.T. Differential antithrombotic effects of tissue factor pathway inhibitor and cyclooxygenase-1 gene transfer in a porcine carotid injury model (Abstract). Regulation of Prostacyclin Synthesis in Vascular Smooth Muscle Cells, Atherosclerotic Arteries, and Vein Grafts Compared to the synthesis of nitric oxide in the healthy and damaged blood vessel wall, relatively little is known about the vascular regulation of prostacyclin. We recently reported that adenoviral gene transfer of cyclooxygenase (COX)-1 to balloon-injured arteries of atherosclerotic rabbits, which lack the LDL receptor, and to venous grafts at the time of arterial bypass prevented thrombosis and promoted a larger lumen area with improved blood flow at 4 weeks after gene transfer. These observations in atherosclerotic animal models expand our earlier observations of COX-1 gene transfer in angioplasty-injured porcine arteries and raise additional questions regarding the mechanism of persistent lumen enlargement ("remodeling") induced by only short-lived adenoviral gene expression. In collaboration with Drs. Kenneth K. Wu and James T. Willerson, we recently observed that in human and rabbit vascular smooth muscle cells combined gene transfer of COX-1 and prostacyclin synthase (PGIS) markedly enhanced prostacyclin and cAMP synthesis compared to gene transfer of COX-1 alone. In contrast, overexpression of PGIS alone only marginally increased prostacyclin synthesis. We are currently examining the molecular basis of this finding, specifically the hierarchy and regulation of enzymes involved in the catalysis of prostacyclin and prostaglandin E2 in vascular smooth muscle cells, atherosclerotic arteries, and vein grafts under hypercholesterolemic conditions. Recent Publications and Abstracts Related to this Project Zoldhelyi, P., McNatt, J., Xu, X.-M., Meidell, R., Loose-Mitchell, D., Willerson, J.T., Wu, K.K. Prevention of arterial thrombosis by adenovirus-mediated transfer of cyclooxygenase gene. Zoldhelyi, P., McNatt, J., Shelat, H.S., Chen, Z.-Q., Willerson, J.T. Differential antithrombotic effects of tissue factor pathway inhibitor and cyclooxygenase-1 gene transfer in a porcine carotid injury model (Abstract). Zoldhelyi, P., Chen, Z.-Q., Shelat, H.S., McNatt, J.M., Willerson, J.T. Adenoviral Gene Transfer of cyclooxygenase-1 improves luminal area and blood flow after carotid balloon injury in atherosclerotic Watanabe rabbits (Abstract). Functions of E2F-1 in Vascular Disorders E2F is a family of transcription factors, which, upon hyperphosphorylation of Rb, promotes entry of cells into the S-phase. Ordinarily, this marks the beginning of DNA synthesis and cell replication. E2F-1 however, appears to be distinct from other members of the E2F family in that S-phase entry is followed by rapid development of apoptotic death. In this project, we try to understand the function and regulation of E2F-1 in vascular smooth muscle cells and in common disorders of the blood vessel wall. In adenoviral gene transfer studies, we have observed that overexpressed E2F-1 induces caspase activity and apoptosis in human coronary vascular smooth muscle cells and protects venous bypass grafts in hypercholesterolemic rabbits from the development of atherosclerosis. Gene transfer of E2F-1 also reduced intimal hyperplasia and atherosclerotic lesion formation after carotid balloon angioplasty in hypercholesterolemic rabbits. We are currently examining how overexpressed E2F-1 engages vascular cells in apoptosis. In related studies, we investigate the role of endogenous E2F-1 in the regulation of intimal hyperplasia and atherosclerosis, studying mice with inactivated E2F-1 gene. Recent Publications and Abstracts Related to this Project Shelat, H.S., Liu, T.-J., Vida, T., Dillard, P.M., Willerson, J.T., Zoldhelyi, P. Growth suppression of human coronary vascular smooth muscle cells by gene transfer of the transcription factor, E2F-1. Eichstaedt H.C., Nolden L.K., ShelatH.S., Liu T.J, Willerson J.T., ZoldhelyiP. Gene transfer of the transcription factor E2F-1 to bypass vein grafts reduces neointima formation in hypercholesterolemic rabbits. Chen Z.-Q., Shelat H.S., Chou M.F., Krajcer A.M., Dillard P.D., Clubb F.J., Willerson J.T., Zoldhelyi P. Gene transfer of E2F-1 induce apoptosis in vascular smooth muscle cells and prevents atherosclerotic lesion formation after balloon injury in hypercholesterolemic rabbits (Abstract). Additional Publications and Abstracts Zoldhelyi, P., Beck, P.J., Robert, J., Bjercke, R.J., Ober, J.C., Hu, X., McNatt, J.M., Akhtar, S., Ahmed, M., Clubb, F.J. Jr., Chen, Z-Q, Dixon, R.A.F., Yeh, E.T.H., Willerson, J.T. Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor. Zoldhelyi, P., McNatt, J..M., Shelat, H.S., Dillard, P., Wun, T-C, Reese, T., Willerson, J.T. Adenovirus-mediated gene transfer of recombinant tissue factor pathway inhibitor in vitro and in vivo. (Abstract). Feng, J., Chou, M.F., Shelat, H.S., Zoldhelyi, P. Role of p21, p53, and proliferating-cell nuclear antigen in growth regulation by nitric oxide (Abstract). Zoldhelyi, P., Eichstaedt, H.C., Jax, T, McNatt, J.M., Chen, Z-Q, Shelat, H.S., Willerson, J.T. The emerging clinical potential of gene therapy. Willerson, J.T. and Zoldhelyi, P. Future directions of thrombolysis. Chen, Z.-Q., Shelat, H.S., McNatt, J.M., Willerson, J.T., Zoldhelyi, P.: Recombinant adenoviral vectors do not increase thrombosis and neointima formation at sites of arterial injury: Importance of hypercholesterolemia. Willerson J.T., Pasceri V., Chen Z.-Q., Zoldhelyi P. Beyond platelet glycoprotein IIb/IIIa receptor antagonists: protection against thrombosis. In: Ferguson J.J., Chronos N., Harrington R. (eds.) Jax, T.W., Yang, H., Willerson, J.T., Zoldhelyi, P. Tissue factor in endothelial and vascular smooth muscle cells is unregulated by thromboxane A2 (Abstract). Jax, T.W., Eichstaedt, H.E., Lichtenberg, M., Willerson, J.T., Zoldhelyi, P.: Gene therapy approaches for thrombotic disorders. For a biography of Wafic Said visit www.waficsaid.com |
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