Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

Abstract

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.0 Ϯ 0.2 M when monkeys were fed normal diet to 10.6 Ϯ 2.6 M when they were fed modified diet (mean Ϯ SE; P ϭ 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 Ϯ 9% in monkeys fed modified diet, compared with 14 Ϯ 11% in monkeys fed normal diet ( P ϭ 0.008). Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 Ϯ 15% in hyperhomocyst(e)inemic monkeys ( P ϭ 0.03). We conclude that diet-induced moderate hyperhomocyst ( IntroductionModerate elevation of plasma homocyst(e)ine 1 concentration is associated with stroke, peripheral vascular disease, and myocardial infarction (1). Like hypercholesterolemia, hyperhomocyst(e)inemia is caused by both genetic and dietary factors and may possibly contribute to vascular disease in a large number of patients (2). Unlike hypercholesterolemia, hyperhomocyst(e)inemia has not been demonstrated to be a sufficient stimulus for development of atherosclerosis per se, but it appears to predispose to complications and perhaps progression of atherosclerosis. Plasma homocyst(e)ine concentration can be decreased by dietary supplementation with folic acid, which suggests that hyperhomocyst(e)inemia may be a treatable risk factor for vascular disease (1, 2).Mechanisms responsible for the association between hyperhomocyst(e)inemia and vascular disease are poorly understood. Results of studies with cultured endothelial cells suggest that homocysteine may impair vasomotor regulatory and antithrombotic properties of vascular endothelium. Exposure of cultured endothelial cells to homocysteine impairs nitric oxide-mediated inhibition of platelet aggregation (3) and inhibits thrombomodulin-dependent activation of protein C, a clinically important anticoagulant (4, 5). Homocysteine also induces cultured endothelial cells to express procoagulant molecules (6, 7) and alters binding of tissue plasminogen activator to endothelium (8). These effects of homocysteine in tissue culture suggest that endothelial dy...

Impaired Homocysteine Metabolism and Atherothrombotic Disease

“…It has also been reported that homocysteine level is related to the extent of atherosclerosis in coronary and peripheral arteries (Chao et al, 1999b;van den Berg et al, 1996;Verhoef et al, 1997b;von Eckardstein et al, 1994). Third, as we will detail below (see "Potential Pathogenic Mechanisms of Hyperhomocysteinemia"), our own work (Durand et al, 1997a) and the work of Lentz et al (1996) and Bellamy et al (1998) give experimental evidence that moderate hyperhomocysteinemia, which leads to vascular dysfunction, might increase the cardiovascular risk independently of other risk factors.…”

Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways

“…Increased dietary methionine or deficiencies of folic acid and vitamin B6 and/or vitamin B12 can lead to hyperhomocysteinemia in humans (43)(44)(45) and animals (32,35,46,47). However, the mechanisms by which elevated levels of homocysteine promote the pathological changes associated with hyperhomocysteinemia are poorly understood.…”

Homocysteine and Malondialdehyde as Predictors of Restenosis Following Percutaneous Coronary Intervention

“…Lentz et al (1996) demonstrated that monkeys that were fed a diet that effectuated moderate hyperhomocysteinemia experienced an increase in vascular dysfunction analogous to that observed in atherosclerotic monkeys. Similarly, Harker et al (1976), upon studying baboons that were administered uninterrupted intravenous infusions of homocysteine, concluded that homocysteine was a causative agent for the development of patchy vascular endothelial injury and intimal smooth muscle cell lesions which correlated to the early atherosclerotic fatty streak lesion observed in humans.…”

“…It has been demonstrated by Lentz and Sadler (1991) that homocysteine precisely and irreversibly deactivates thrombomodulin and protein C. In addition, a study involving the in-vivo thoracic aorta of monkeys with diet-induced hyperhomocysteinemia reported a thrombomodulin dependent protein C activation decrease by 35% compared to controls (Lentz et al 1996). Therefore, the ability of homocysteine to inhibit thrombomodulin and thus protein C activity may have the effect of endothelial thrombus formation ( Lee and Prasad, 2002;Griffin et al 1995).…”