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cGMP regulation of vascular smooth muscle differentiation

Institution: University of California, San Diego
Investigator(s): Renate Pilz, M.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0020 Award: $403,818
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Cigarette smoke is one of the most potent and wide-spread environmental health risks that human being are exposed to, and active or passive smoking is responsible for more than 1000 deaths each day in the United States. The majority of cigarette smoking-induced deaths are due to cardiovascular disease, including heart attacks and strokes. Recent research suggests that cigarette smoking causes the generation of unhealthy oxygen radicals, which, among other things, interfere with the generation of nitric oxide (NO). NO is a small gas molecule normally formed in the blood vessel wall that regulates the synthesis of the second messenger molecule cGMP, which in turn activates an enzyme called cGMP-dendent protein kinase (G-kinase). This NO/cGMP/G-kinase signaling pathway regulates the behavior of smooth muscle cells which line normal and diseased blood vessels. Decreased activity of this pathway is observed in smokers and may promote the narrowing, scarring and hardening of blood vessels that is the hallmark of atherosclerosis, leading to heart attacks and strokes. In contrast, increased activity of the pathway may be protective and prevent blood vessel hardening and narrowing. It has been known for some time that the NO/cGMP/G-kinase pathway regulates the blood pressure through changes in smooth muscle tone. Recently, it has become clear that G-kinase may also counteract the changes that vascular smooth muscle cells undergo after vascular injury and during atherosclerosis. G-kinase modulates the function of smooth muscle cells through changes in gene expression. We propose to study the mechanisms whereby G-kinase reverses the loss of smooth muscle-specific gene expression that is observed in injured blood vessels. We found that G-kinase is part of a complex composed of multiple proteins, including transcription factors responsible for the expression of smooth muscle-specific genes. We will study this complex in detail and determine what role it plays in controlling the changes in gene expression that occur in smooth muscle cells when the blood vessel wall is diseased. These studies will enhance our understanding of how cigarette smoking promotes the development of atherosclerosis and what role the NO/cGMP/G-kinase signaling pathway plays in the development of cardiovascular disease.

A cysteine-rich LIM-only protein mediates regulation of smooth muscle-specific gene expression by cGMP-dependent protein kinase.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Zhang T, Zhuang S, Casteel DE, Looney DJ, Boss GR, Pilz RB ART
Yr: 2007 Vol: Nbr: 282 Abs: Pg: 33367-33380