Elsevier

Life Sciences

Volume 61, Issue 13, 22 August 1997, Pages 1205-1215
Life Sciences

MINIREVIEW
HOMOCYSTEINE AND VASCULAR DYSFUNCTION

https://doi.org/10.1016/S0024-3205(97)00392-5Get rights and content

Abstract

Elevated plasma levels of homocysteine and disulfide adducts of homocysteine (collectively termed “homocyst(e)ine”) are associated with increased risk of thrombotic and atherosclerotic vascular disease. It is still not evident, however, whether moderately elevated plasma homocyst(e)ine concentration per se is a cause, or rather just a marker for an associated condition that may predispose to development of vascular disease or its complications. This distinction has important clinical consequences, since dietary intervention to lower plasma homocyst(e)ine has been proposed as a global strategy to decrease the prevalence of vascular disease. Studies of cultured cells in vitro have led to the hypothesis that homocysteine may predispose to vascular disease by altering the normally antithrombotic and vasoprotective phenotype of vascular endothelium, perhaps through a mechanism that involves generation of peroxides and other reactive oxygen species. Recent findings in animal and human models of moderate hyperhomocyst(e)inemia provide support for some aspects of this hypothesis. Endothelial dysfunction in hyperhomocyst(e)inemia provide support for some aspects of this hypothesis. Endothelial dysfunction in hyperhomocyst(e)inemia may contribute to development of atherosclerosis and predispose to complications such as thrombosis and vasospasm. Important questions to be addressed in future investigations include the relative importance of homocysteine versus associated conditions (such as folate deficiency) in the etiology of vascular dysfunction, the role of homocysteine-induced oxidant stress, and the potential benefits of lowering plasma homocyst(e)ine levels through dietary supplementation with B vitamins.

Section snippets

Homocysteine Metabolism

Homocysteine is a thiol amino acid that is generated from metabolism of methionine. Cellular levels of homocysteine are regulated by availability of methionine, remethylation of homocysteine to methionine, and transsulfuration of homocysteine to cysteine (Fig. 1). Homocysteine is formed from hydrolysis of S-adenosylhomocysteine, which is produced as a product of methyl transfer reactions that utilize S-adenosylmethionine as a methyl donor. Remethylation to methionine is catalyzed in most

Causes of Hyperhomocyst(e)inemia

Extracellular homocyst(e)ine is derived from the cellular export of homocysteine [15]. Plasma concentrations of homocyst(e)ine are regulated by genetic and dietary factors. Mean fasting levels are usually ≤10 μM, with the 95th percentile at approximately 15 μM [16]. Concentrations are higher in males than females [17].

Severe hyperhomocyst(e)inemia (fasting plasma homocyst(e)ine concentration > 100 μM) occurs classically in patients with hereditary homocystinuria due to homocygous CBS

Association of Hyperhomocyst(e)inemia with Vascular Disease

Severe hyperhomocyst(e)inemia due to homozygous CBS deficiency predisposes to both atherosclerotic vascular disease and venous thrombosis, with approximately 50% of patients developing a clinically significant vascular event prior to age 30 [18]. Premature vascular disease also is seen in other inherited metabolic disorders that produce severe hyperhomocyst(e)inemia, which suggests that predisposition to vascular disease may result directly from elevated concentrations of homocyst(e)ine 1, 14,

Mechanisms of Vascular Dysfunction in Hyperhomocyst(e)inemia

Although many studies have investigated potential adverse effects of homocysteine on blood vessels, the mechanisms responsible for vascular dysfunction in hyperhomocyst(e)inemia remain poorly understood. Much of the recent work in this field has focussed on two areas: functional abnormalities of vascular endothelium and the potential role of oxidant stress.

Questions for Future Studies

Notwithstanding the considerable recent progress in delineating the epidemiology and physiology of moderate hyperhomocyst(e)inemia, several important questions remain to be answered about the association between homocysteine and vascular dysfunction. One goal of future studies will be to determine the relative role in vascular dysfunction of hyperhomocyst(e)inemia caused by genetic defects (such as heterozygosity for CBS deficiency or homozygosity for the C677T mutation in MTHFR) versus

Acknowledgements

Supported in part by the Office of Research and Development, Department of Veterans Affairs, National Institutes of Health grants NS-24621, DK-25295, and RR-00163, and the Roy J. Carver Charitable Trust.

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