Vascular C-Reactive Protein in the Pathogenesis of Coronary Artery Disease:Role of Vascular Inflammation and Oxidative Stress

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Abstract:

Atherosclerosis is considered to be a chronic inflammatory disease. Vascular inflammation occurs in response to injury induced by various stimuli, such as oxidative stress, shear stress, infection, and so on. This concept is supported by the recent clinical findings that C-reactive protein (CRP) is an independent risk factor for coronary heart disease. CRP, which was originally identified as a protein that could precipitate the C-polysaccharide of pneumococcal cell walls, has been widely used as a clinical marker of the state of inflammation, since its production by hepatocytes increases during the acute phase of the inflammatory response. Recent investigations have provided two new concepts for the research field of CRP, namely, its extra-hepatic production and its potent biological activities such as the induction of adhesion molecules and chemokines. Recently, we demonstrated that smooth muscle cells and macrophages in coronary arteries expressed CRP protein and mRNA, as evaluated using coronary specimens of coronary artery disease (CAD) patients obtained by atherectomy. The expression of vascular CRP was closely associated with NAD(P)H oxidase, an important enzymatic origin of reactive oxygen species (ROS) in vessel walls. Furthermore, CRP directly up-regulated NAD(P)H oxidase p22phox and enhanced ROS generation in cultured coronary artery smooth muscle cells. Thus, vascular CRP is likely to be a direct participant in vascular inflammation and lesion formation via its potent biological effects. Since lysophosphatidylcholine, a major atherogenic lipid of oxidized LDL, was reported to activate vascular NAD(P)H oxidase, we speculate that there is a vicious circle consisting of vascular NAD(P)H oxidase, ROS and oxidized LDL. Since phagocytic NAD(P)H oxidase is at the first line of the host defense system, it is important to selectively suppress vascular NAD(P)H oxidase in the localized inflammatory lesions in therapeutic strategies for CAD. In this review, we will discuss the roles of vascular CRP and NAD(P)H oxidase in the pathogenesis of CAD from the viewpoint of oxidative stress.





Keywords: NAD(P)H oxiadase; acute coronary syndrome; superoxide

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152906779010719

Affiliations: National Cardiovascular Center Research Institute. Department of Vascular Physiology, 5-7-1, Fujishirodai, Suita City, Osaka 565-8565, Japan.

Publication date: December 1, 2006

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  • Cardiovascular & Hematological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in cardiovascular and hematological disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cardiovascular and hematological disorders. As the discovery, identification, characterization and validation of novel human drug targets for cardiovascular and hematological drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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