Homocysteine-induced inhibition of nitric oxide production in platelets: a study on healthy and diabetic subjects

Abstract

Moderate increases in the plasma concentrations of homocysteine are associated with an increased incidence of arteriosclerosis and cardiovascular disease [1]. Homocysteine could exert adverse vascular effects by a number of mechanisms: production of reactive oxygen species caused by auto-oxidation, reduced endothelial generation of nitric oxide (NO) and/or enhancement of vascular smooth muscle cell proliferation [2]. Recent data have shown that flowmediated vasodilation is reduced in the presence of methionine-induced mild hyperhomocysteinemia and that this endothelial dysfunction is because of impaired NO activity without change of oxidative status [3]. Moreover, the exposure to homocysteine increases the interaction of leukocytes and endothelium through the expression of the endothelial cell adhesion molecules (P-selectin and ICAM-1) and the up regulation of CD18 expression in neutrophils [4]. A concomitant treatment with an NO donor reduces these homocysteine effects [4].Platelet-rich thrombus formation has been found in homocysteine-induced atherosclerotic lesions but Diabetologia (2001) Abstract Aims/hypothesis. The molecular mechanisms involved in the platelet activation observed in hyperhomocysteinemia are not known. We aimed to discover if homocysteine concentrations are associated with abnormal platelet nitric oxide production in healthy and diabetic subjects. Methods. The study cohort included 28 patients with Type I (insulin-dependent) diabetes mellitus, 30 patients with Type II (non-insulin-dependent) diabetes mellitus, and 34 healthy subjects. Homocysteine plasma concentrations were measured by high-performance liquid chromatography. Platelet nitric oxide production was measured using a nitric oxide meter before and after a 3-h incubation with 100 mmol/l homocysteine. Stimulation experiments were done in vitro by the addition of a-thrombin (0.2 U/ml).Results. Basal platelet nitric oxide production was lower in diabetic patients than in healthy subjects. Nitric oxide release was reduced by in vitro homocysteine incubation, being lower in platelets from diabetic patients than in platelets from control subjects. Thrombin increased nitric oxide synthesis in platelets from healthy subjects both in the presence and absence of homocysteine. In diabetic subjects thrombin increased nitric oxide release in the absence of homocysteine. But in the presence of homocysteine the response was reduced. An inverse relation was found between plasma homocysteine levels and basal platelet nitric oxide release in diabetic and healthy subjects. Conclusion/interpretation. Homocysteine could exert its atherogenic action in healthy and diabetic subjects partly by inhibiting platelet nitric oxide production with the subsequent increased platelet activation and aggregation. [Diabetologia (2001) 44: 979±982]

Total plasma homocysteine is associated with hypertension in Type I diabetic patients

“…Results from experimental studies which showed that hyperhomocysteinaemia interferes with the vasodilator and antithrombotic function of nitric oxide [29,30] and with the peroxide-mediated effects on arterial prostacyclin synthesis [31] were supported by clinical findings. Recently, an inverse relation between a range of tHcy concentrations and endothelium-dependent coronary blood flow was documented [32].…”

Epidemiology of Homocysteine as a Risk Factor in Diabetes

“…However, NO production in platelets from diabetic patients was lower than that in nondiabetic patients. 47 Thus, no consistent pattern regarding the relationship between homocysteine and NO availability/vascular tone emerges from studies performed to date.…”

“…40 Whether the factors discussed in aggregate lead to differences in plasma homocysteine level between patients with diabetes and healthy subjects is unclear. Some authors have reported higher homocysteine levels in diabetic patients, 15,16,[41][42][43][44][45][46] while others have found similar 14,45,[47][48][49][50] or even lower levels. 35,[51][52][53][54][55][56] These discrepancies may be due mainly to the fact that most studies did not account for folate status and renal function, the two most important determinants of plasma homocysteine level.…”

Mechanisms of Ischemic Induced Neuronal Death and Ischemic Tolerance

“…It has been reported that hyperhomocysteinemia may also be associated with the incidence of ischemic brain stroke (Refsum et al, 1998), mainly due to pleiotropic activity of homocysteine and acceleration of atherosclerotic changes (Refsum et al, 1998;Thambyrajah et al, 2000). In fact, Hcy suppresses NO production by endothelial cells (Upchurch et al, 1997) and platelets (Mutus et al, 2001) and increases generation of reactive oxygen species (ROS) by the release of arachidonic acid from platelets (Signorello et al 2002). It also inhibits glutathione peroxidase (Upchurch et al, 1997), and thus stimulates proliferation of endothelial cells (Jeremy et al, 1999;Domagala et al, 1998).…”