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(Stroke. 2004;35:345.)
© 2004 American Heart Association, Inc.

Advances in Stroke 2003

Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

Frank M. Faraci, PhD Steven R. Lentz, MD, PhD

From the Departments of Internal Medicine (F.M.F., S.R.L.) and Pharmacology (F.M.F.), Cardiovascular Center, University of Iowa Carver College of Medicine, Veteran Affairs Medical Center (S.R.L.), Iowa City, Iowa.

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

Key Words: Advances in Stroke • hyperhomocysteinemia

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

An elevated circulating concentration of the sulfur-containing amino acid homocysteine, hyperhomocysteinemia, produces complex changes within the blood vessel wall. In the peripheral circulation, these changes include oxidative stress, proinflammatory effects such as expression of tumor necrosis factor- and inducible nitric oxide (NO) synthase (iNOS), and endothelial dysfunction.^1–6 Hyperhomocysteinemia-induced oxidative stress may occur as a result of decreased expression and/or activity of key antioxidant enzymes as well as increased enzymatic generation of superoxide anion (the precursor for multiple reactive oxygen and reactive nitrogen species).^2,4

Do hyperhomocysteinemia-induced changes occur in the cerebral circulation and why are they potentially important? Hyperhomocysteinemia is a an emerging risk factor for carotid artery disease (atherosclerosis) and stroke and is associated with Alzheimer’s disease and vascular dementia.^7–11 It was not until relatively recently, however, that experimental studies began to define the impact of hyperhomocysteinemia on cerebral vascular biology and the molecular mechanisms that account for these changes. This work has been facilitated by the development of mouse models with genetic alterations in different components of the homocysteine metabolic pathway (see below).

Early work in the cerebral microcirculation observed that acute local administration of a very high concentration of homocysteine (1 mmol/L) in the presence of exogenous Cu²⁺ produced superoxide-mediated reductions in resting cerebral blood flow (CBF) as well as attenuation of endothelium-dependent and NO-mediated responses.¹² Our group was among the first to show that mild chronic hyperhomocysteinemia produces endothelial dysfunction in the carotid artery.^1,13 Moderate hyperhomocysteinemia, induced by acute methionine loading, produces impaired autoregulatory responses in older . . . [Full Text of this Article]

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