This competing renewal application will continue to explore the role of kallistatin in hypertension. Kallistatin was first discovered in our laboratory as tissue kallikrein-binding protein, a new plasma serine proteinase inhibitor. During the current funding period, many important findings have emerged in support of the hypothesis that kallistatin has a role in the regulation of blood pressure and vascular biology. We found that kallistatin is a potent vasodilator that directly causes a transient reduction of blood pressure, vasorelaxation in isolated aortic rings, and vasodilation of the renal vasculature in perfused rat kidney. Transgenic mice overexpressing kallistatin are hypotensive and somatic gene delivery of kallistatin caused a significant and prolonged reduction of blood pressure in spontaneously hypertensive rats. Kallistatin may regulate vascular cell growth, as its expression levels increase markedly in balloon-injured rat artery and exogenous kallistatin stimulates the proliferation of primary cultured vascular smooth muscle cells.
The specific aims are: 1) to analyze structural and functional relationships of kallistatin on vascular cell proliferation and vasorelaxation by site-directed mutagenesis and domain substitutions; 2) To identify, characterize and clone new kallistatin-binding protein in blood vessels; 3) To analyze the role of kallistatin in vascular cell proliferation and migration with a balloon-injured rat artery model by antisense kallistatin gene delivery and by ribozyme inhibition strategy; 4) To study the role of kallistatin in blood pressure regulation by delivery of the kallistatin gene in spontaneously hypertensive rats, and 5) To analyze the promoter region of the kallistatin gene and genetic linkage and association between the human kallistatin gene and hypertension in selected hypertensive populations, affected siblings and family pedigrees. The proposed work could significantly advance our understanding of the role of kallistatin in blood pressure regulation and vascular function and may provide new tools and technologies for improved detection and treatment of hypertension and cardiovascular diseases.
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