Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus induces a characteristic platelet hyperactivity that might be due to several factors including oxidativ stress and abnormal intracellular Ca2+ homeostasis. Hyperhomocysteinaemia is considered a risk factor in the development of thrombosis although its effect on platelet function and the mechanisms involved are still poorly understood. Here we show tha homocysteine induce a concentration-dependent increase in endogenous production of reactive oxygen species (ROS), which was significantly greater in platelets from diabetic patients than in controls. Platelet treatment with homocysteine resulted in Ca2+ release from the dense tubular system and the acidic stores. Ca2+ mobilization-induced by homocysteine consisted in two components, an initial slow increase in intracellular free Ca + concentration ([Ca +]i) and a rapid and marked increase in [Ca2+]i, th second leading to the activation of platelet aggregation. As well as ROS generation, Ca2+ mobilization and platelet aggregation were significantly greater in platelets from diabetic donors than in controls, which indicate that platelets from diabetic donors are more sensitive to homocysteine. These findings, together with the hyperhomocysteinaemia reported in diabetic patients, strongly suggest that homocysteine might be considered a risk factor in the development of cardiovascular complications associated to type 2 diabetes mellitus.

Reconciling the Evidence on Serum Homocysteine and Ischaemic Heart Disease: A Meta-Analysis

“… [7] A Medline literature search identified 22 studies on the effect of homocysteine on platelet function [8] – [29] . Seventeen studies showed a statistically significant (p<0.05) effect of homocysteine on increasing prothrombotc platelet function (increased platelet activation, [8] – [16] thromboxane production [17] – [20] or platelet aggregation [21] – [22] ), 4 were inconclusive [25] – [28] and 1 showed an effect in the opposite direction. [29] The evidence that homocysteine increases prothrombotic platelet function is thus persuasive.…”

Melatonin, as an adjuvant‐like agent, enhances platelet responsiveness

“…thrombin, involves the activation of several of intracellular signalling pathways, including Ca 2+ mobilization. It is well known that reactive oxygen species alter Ca 2+ signaling in platelets [19,20], and subsequently platelet aggregation [21], which further suggests that administration of melatonin either by direct effects on platelet binding sites or through its antioxidant actions might modulate/protect platelet function. Here, we have investigated the effect of administration of melatonin as an adjuvant of the vaccine against A1 and C strains of D. nodosus on platelet intracellular Ca 2+ homeostasis and aggregation in response to the physiological agonist, thrombin.…”

Impaired Homocysteine Metabolism Associated with High Plasma Interleukin- 17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India

“…4,5 Being at the axis of DNA synthesis and methyla-tion cycle, homocysteine metabolism (in close proximity with MTHFR) plays an important role in lipid metabolism, immune activation and other biological reactions. [6][7][8] Hypomethylation of homocysteine has been associated with dyslipidemia, atherosclerosis, hypertension, and all cause mortality in different populations of the world. [8][9][10][11] Also, hyperhomocysteinemia is known to suppress the function of Foxp3+ Tregs cells in murine models, 12 suggesting an important link between homocysteine metabolism and Foxp3.…”