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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:371.)
© 2003 American Heart Association, Inc.

Editorials

Hyperhomocysteinemia

A Million Ways to Lose Control

Frank M. Faraci

From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City.

Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E315-GH, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242-1081. E-mail frank-faraci@uiowa.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Elevated plasma levels of the amino acid homocysteine increase the risk for atherosclerosis, stroke, myocardial infarction, and possibly Alzheimer’s disease. In relation to vascular biology, many studies suggest that endothelial dysfunction contributes to the complex changes that occur within the vessel wall during hyperhomocysteinemia (HHCy). The underlying molecular mechanisms that are activated during HHCy have just begun to be understood.

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With regard to endothelial dysfunction, a major focus has been on mechanisms that impair NO-mediated signaling within the vessel wall (Figure). NO produced by the endothelial isoform of NO synthase (eNOS) is known to be the major endothelium-derived relaxing factor in blood vessels. Endothelium-dependent relaxation is impaired during HHCy in experimental animals and humans, in both large arteries and microvessels.^1–8 Mechanisms that mediate this impairment are very complex, as they potentially involve every major component of eNOS signaling (Figure). An intriguing mechanism now receiving increased attention involves inhibiting the activity of eNOS by increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases.^9,10

View larger version (32K): [in this window] [in a new window]   Schematic illustration of selected changes within the vessel wall in response to HHCy. HHCy produces decreased activity of CAT-1 (the transporter for L-arginine, the substrate for eNOS),34 increased expression of caveolin-1, an eNOS-binding protein that inhibits activity of eNOS,35,36 and in some studies, reduced expression of eNOS.37 Activity of eNOS can also be inhibited by asymmetric dimethylarginine ADMA. Homocysteine increases levels of superoxide (O2-) by activating NAD(P)H oxidase and iNOS as well as by inhibiting expression . . . [Full Text of this Article]

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