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Mechanisms by which tobacco accelerates atherosclerosis

Institution: Stanford University
Investigator(s): John Cooke, M.D., Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0128 Award: $675,731
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
The use of tobacco is a major risk factor for atherosclerosis ("hardening of the arteries"), as is hypercholesterolemia (high blood cholesterol), hypertension (high blood pressure), and diabetes mellitus (high blood sugar). Work in our laboratory indicates that hypercholesterolemia, hypertension, and diabetes mellitus may adversely affect the vessel wall by causing an oxidative stress. The oxidative stress on the vessel wall causes the lining of the vessel (the endothelium) to change from what is normally a teflon like coating, to something which resembles velcro. Certain cells within the blood begin to stick to the endothelium; the first step in atherosclerosis ("hardening of the arteries").

Recently our laboratory has discovered that nicotine (one of the active components of tobacco) has effects on the vessel wall similar to those of hypercholesterolemia, hypertension and diabetes. This project will determine if there is a common pathway by which high cholesterol, high blood sugar, high blood pressure, and tobacco smoking may cause hardening of the arteries. Furthermore, we have learned that the blood vessel produces a molecule that can protect it from atherosclerosis. This molecule is endothelium derived nitric oxide. We have found that nitric oxide restores the endothelium so that it becomes less adhesive (more like teflon and less like velcro). We have developed methods to enhance the release of nitric oxide from the vessel wall in animals and humans. We will determine if these methods can reverse the effects of tobacco smoke. We anticipate that this scientific study may lead to new insights and new therapies for atherosclerosis.

Dietary L-arginine reverses the inhibitory effect of asymmetric dimethylarginine on angiogenesis in hypercholesterolemia
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Hoai KVH, et al ABS
Yr: 1999 Vol: Nbr: Abs: 407-2 Pg:

Asymmetric dimethylarginine inhibits basic fibroblast growth factor induced angiogenesis
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Jang J, ABS
Yr: 0 Vol: Nbr: Abs: 1041-31 Pg:

endothelial growth factor-C fails to induce fibrovascular growth
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Jang J, et. al. ABS
Yr: 1999 Vol: Nbr: Abs: 1041-26 Pg:

Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis
Periodical: Nature Medicine Index Medicus:
Authors: Cooke JP ART
Yr: 2001 Vol: 7 Nbr: 7 Abs: Pg: 833-839

Nicotine stimulates wound healing in diabetic mice.
Periodical: American Journal of Pathology Index Medicus:
Authors: Jacobi J, Jang JJ, Sundram U, Fajardo L, and Cooke JP ART
Yr: 2002 Vol: 161 Nbr: 1 Abs: Pg: 97 - 104

Nitric oxide and angiogenesis.
Periodical: Circulation Index Medicus:
Authors: Cooke JP, and Losordo DW ART
Yr: 2002 Vol: 105 Nbr: 18 Abs: Pg: 2133 - 2135

A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors.
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Heeschen C, Weis M, and Cooke JP ART
Yr: 0 Vol: Nbr: Abs: Pg: