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Dysregulation of VSMC signaling induced by nicotine

Institution: Stanford University
Investigator(s): Philip Tsao, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0298 Award: $683,510
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Heart attacks are the number one cause of death in the Western Hemisphere. The most common cause of heart attacks is atherosclerosis, or "hardening" of the arteries. It is well accepted that individuals that smoke tobacco products have increased risk for developing atherosclerosis. Upon examination of diseased vessels, one sees abnormal growth of blood vessel cells causing narrowing of vessels so as to compromise the flow of blood. One cell type that is thought to participate in this growth is the vascular smooth muscle cell. These cells are an important component of the normal blood vessel, providing structural integrity as well as giving the muscular ability to dilate and constrict. Several risk factors for atherosclerosis such as hypertension and diabetes can cause increased growth of vascular smooth muscle cells. These diverse risk factors are thought to initiate common signals within the cell to initiate the growth program. One of these common signals is oxidative stress. The oxidative stress causes the vascular smooth muscle cell to produce and secrete a variety of proteins that result in the growth of the originating as well as neighboring cells. Another result of this growth pattern is the deposition of structural proteins that, in the normal blood vessel, aid in strengthening the vessel. However, produced in excess, these proteins can cause abnormal stiffening of the arteries and veins.

Recently our laboratory has discovered that nicotine, one of the active components of tobacco, has similar effects on the vessel wall. We believe that nicotine may initiate oxidative stress in vascular smooth muscle cells and thereby accelerate the progression of atherosclerosis. Our preliminary studies indicate that nicotine enhances the production of toxic oxygen-derived free radicals and that antioxidants can inhibit the nicotine-induced growth program. The project outlined in this proposal will confirm this observation and explore it in greater depth. Moreover, we will test the hypothesis that nicotine can alter the underlying expression pattern of defense molecules within the vascular smooth muscle cell, thereby leaving the cell more vulnerable to injury. We have developed various models to imitate the effects of nicotine on blood vessel cells and evaluate the effects upon cell growth in highly reproducible assays. It is intriguing to think that there may be a common mechanism by which high blood pressure, high blood sugar (diabetes), and tobacco smoking may cause hardening of the arteries. Exploration into what the pathways are involved in these processes may lead to the design of specific drugs which can target areas which may be more prone to form atherosclerotic plaques.

Does gluocorticoid dysregulation contribute to the link between cigarette smoking and insulin resistance? Reply.
Periodical: Journal American Coll Cardiol Index Medicus:
Authors: Reaven GM, Tsao PS ART
Yr: 2003 Vol: 42 Nbr: Abs: Pg: 771-772