Elsevier

Clinical Biochemistry

Volume 36, Issue 6, September 2003, Pages 431-441
Clinical Biochemistry

Hyperhomocysteinemia and its role in the development of atherosclerosis

https://doi.org/10.1016/S0009-9120(03)00062-6Get rights and content

Abstract

Numerous epidemiological studies have demonstrated that hyperhomocysteinemia (HHcy) is a strong and independent risk factor for cardiovascular disease. HHcy can result from a deficiency in the enzymes or vitamin cofactors required for homocysteine metabolism. Several hypotheses have been proposed to explain the cellular mechanisms by which HHcy promotes cardiovascular disease, including oxidative stress, endoplasmic reticulum (ER) stress and the activation of pro-inflammatory factors. Studies using genetic- and diet-induced animal models of HHcy have now demonstrated a direct causal relationship between HHcy, endothelial dysfunction and accelerated atherosclerosis. These recently established animal models of HHcy provide investigators with important in vivo tools to (i) further understand the cellular mechanisms by which HHcy contributes to endothelial dysfunction and atherosclerosis, and (ii) develop therapeutic agents useful in the treatment of cardiovascular disease.

Introduction

Atherosclerosis, the principal cause of cardiovascular disease and stroke, is a complex, chronic process that is initiated at sites of endothelial cell injury and culminates in the formation of stratified lesions of the arterial wall [1], [2], [3], [4], [5]. Subendothelial infiltration of monocytic cells, proliferation and migration of smooth muscle cells, cholesterol deposition, and elaboration of extracellular matrix are hallmark features of atherosclerotic lesions. Cholesterol-laden smooth muscle cells and macrophages, morphologically recognized as foam cells, are observed at all stages of lesion development [6], [7]. The importance of cholesterol and its oxidized derivatives in the pathogenesis of atherosclerosis is supported by studies demonstrating the presence of cholesterol within the lesions from humans and animals [8], [9], [10], [11], [12]. Traditionally, cholesterol and its oxidized derivatives are thought to accumulate in atherosclerotic lesions, thereby contributing to the formation of advanced, multilayered atheromas. Although advanced atherosclerotic lesions cause progressive narrowing of the vessel lumen that can lead to ischemic symptoms, acute coronary syndromes usually result from lesion rupture and thrombosis [1], [2], [3], [4].

Conventional risk factors for cardiovascular disease, including hypercholesterolemia, hypertension, smoking and diabetes, account for approximately 50% of all cases [1], [2], [12]. Evidence now indicates that HHcy, which occurs in approximately 5 to 7% of the general population, is an important, independent risk factor for atherosclerosis and thrombotic disease [13], [14], [15], [16], [17], [18], [19], [20]. Furthermore, up to 40% of patients diagnosed with premature coronary artery disease, peripheral vascular disease or recurrent venous thrombosis have HHcy [13], [14], [15], [16], [17], [18].

In this review article, we will summarize the genetic and nutritional factors that induce HHcy and further examine the clinical evidence implicating HHcy as an independent risk factor for cardiovascular disease. In addition, potential mechanisms by which homocysteine accelerates atherosclerosis will be discussed in light of the important findings recently reported for both genetic- and diet-induced animal models of HHcy.

Section snippets

Genetic and nutritional factors causing HHcy

Homocysteine is a thiol-containing amino acid that is formed during the metabolic conversion of methionine to cysteine (Figure 1). Once synthesized, homocysteine may either be metabolized to cysteine by the transsulphuration pathway or converted back to methionine by the remethylation pathway [16], [19], [20]. Mutations in genes responsible for homocysteine metabolism can result in homocystinuria, a severe form of HHcy [20]. The most common genetic cause of homocystinuria, homozygous

Homocysteine and vascular disease

Patients suffering from homocystinuria develop extensive arterial intimal thickening and fibrous plaques rich in smooth muscle cells and collagen [20], [23], [35]. These fibrous lesions greatly outnumber fatty atherosclerotic lesions in the major arteries of homocystinuric patients and, combined with abnormally accelerated thrombosis, lead to tissue infarction and death at an early age [35]. Venous thrombosis and, to a lesser extent, arterial thrombosis are common in patients with

Inflammatory response

In general, the development and progression of atherosclerosis is considered to be a form of chronic inflammation [1], [2], [3], [11]. In support of these findings, in vitro studies have demonstrated that homocysteine enhances the production of several pro-inflammatory cytokines. Expression of monocyte chemoattractant protein 1 (MCP-1) is increased in cultured human vascular endothelial cells, smooth muscle cells and monocytes treated with homocysteine [43], [44], [45]. MCP-1 is known to

Animal models of hyperhomocysteinemia

Recent findings from genetic- and diet-induced animal models of HHcy have significantly enhanced the status of homocysteine as a risk factor for atherosclerosis. They have also supported and extended many of the proposed in vitro mechanisms and have provided a more physiological perspective on the role of homocysteine in the induction of cardiovascular disease.

Manipulation of plasma homocysteine can be accomplished by dietary and/or genetic approaches. The addition of methionine and/or

Conclusions and questions

HHcy is an independent risk factor for cardiovascular disease. Recent studies have identified three major cellular mechanisms by which HHcy may contribute to the development of endothelial dysfunction and atherosclerosis. They include the induction of pro-inflammatory factors, oxidative stress, and ER stress. Genetic- and diet-induced animal models of HHcy have now demonstrated a causal relationship between HHcy and accelerated atherosclerosis. They have also provided important insights into

Acknowledgements

The author’s work is supported by Research Grants from the Heart and Stroke Foundation of Ontario (T-4005) and the Canadian Institutes of Health Research (MOP-49417). R.C. Austin is a Career Investigator of the Heart and Stroke Foundation of Ontario. We apologize to many of our colleagues whose work could not be directly acknowledged due to space limitations.

Recent studies by Ji and Kaplowitz [126] have demonstrated increased HHcy, ER stress and liver injury in an alcohol-fed mouse model of

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