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Nitric oxide-dependent cell signaling in vascular cells

Institution: University of California, San Diego
Investigator(s): Tanima Gudi, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9KT-0170H Award: $149,557
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards

Initial Award Abstract
Cigarette smoking is a major risk factor for the development of atherosclerosis, with smokers having at least a 2.5-fold increased incidence of coronary heart disease compared with non-smokers. Smoking reduces production of nitric oxide (NO) by endothelial cells, which line the walls of blood vessels. Cigarette smoke has been associated with abnormal endothelial cell and vascular smooth muscle cell function in animal models of atherosclerosis and in passive smokers.

Nitric oxide is the most potent endogenous dilator of blood vessels known and it exerts its actions in a similar manner as anti-anginal drugs, such as nitroglycerin. It activates an enzyme within vascular smooth muscle cells, leading to the production of cyclic guanosine monophosphate (cGMP). Cyclic GMP in-turn activates cGMP-dependent protein kinase (G-kinase), an enzyme which mediates vascular smooth muscle relaxation, but little is known about the downstream effects and targets of G-kinase in vascular smooth muscle cells.

In this study, we propose to examine the changes that take place in vascular smooth muscle cells in response to NO signaling. The proteins or molecules undergoing these changes will be identified and studied. The role of NO as an anti-atherogenic molecule acting via G-kinase will be studied. Proteins activated or inhibited by NO/cGMP signaling in normal and pathological conditions will be identified.

NO/cGMP/G-kinase signaling is important for controlling blood pressure, relaxation of vascular walls and regulating growth, differentiation and migration of vascular cells involved in atherogenesis. Given the importance of nitric oxide, studying and ultimately manipulating the NO/cGMP/G-kinase signal transduction pathway may provide novel therapeutic approaches to limit atherogenesis and other cardiovascular diseases.