Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor

Abstract

Elevated plasma homocysteine accelerates myointimal hyperplasia and luminal narrowing after carotid endarterectomy. N-methyl D aspartate receptors (NMDAr) in rat cerebrovascular cells are involved in homocysteine uptake and receptor-mediated stimulation. In the vasculature, NMDAr subunits (NR1, 2A-2D) have been identified by sequence homology in rat aortic endothelial cells. Exposure of these cells to homocysteine increased expression of receptor subunits, an effect that was attenuated by dizocilpine (MK801), a noncompetitive NMDA inhibitor. The objective of this study was to investigate the existence of an NMDAr in rat vascular smooth muscle (A7r5) cells, and also the effect of homocysteine on vascular dysregulation as mediated by this receptor. Subunits of the NMDAr (NR1, 2A-2D) were detected in the A7r5 cells by using the reverse transcriptase polymerase chain reaction and Western blotting. Homocysteine induced an increase in A7r5 cell proliferation, which was blocked by MK801. Homocysteine, in a dose and time dependent manner, increased expression of matrix metallinoproteinase-9 and interleukin-1beta, which have been implicated in vascular smooth muscle cell migration and/or proliferation. Homocysteine reduced the vascular elaboration of nitric oxide and increased the elaboration of the nitric oxide synthase inhibitor, asymmetric dimethylarginine. All of these homocysteine mediated effects were inhibited by MK801. NMDAr exist in vascular smooth muscle cells and appear to mediate, at least in part, homocysteine-induced dysregulation of vascular smooth muscle cell functions.

Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia

“…In endocardial endothelial denuded myocardium Hcy induces contraction. The mechanism of Hcy mediated cardiac contraction and enhanced CaCl 2 sensitivity in endocardial-endothelium denuded myocardium may suggest Ca 2+ -sensitive Hcy receptor (NMDA-R1, Chen et al, 2005;Qureshi et al, 2005) playing a significant role in Hcy mediated cardiac contractile dysfunction. Therefore, it is important to determine the role of NMDA-R1 in Hcy-mediated cardiac contraction, arrhythmia and failure (Figure 4).…”

“…The increase in iNOS induced sudden cardiomyocyte death and may lead to SCD (Mungrue et al, 2002). NMDA is a major excitatory neurotransmitter, and NMDA-R1 is present in the mammalian central nervous system (CNS, Lalo et al, 2006), in cardiomyocytes (Kraine et al, 1998;Huang & Su, 1999) and the endothelial cells Qureshi et al, 2005). The relative expression of the NMDA-receptor in heart, specifically expression in cardiomyocytes versus endothelial cells and neuronal tissue (sympathetic and parasympathetic nerve endings, for example) is in the order of neuronal >cardiomyocyte >endothelial cells.…”

Effect of homocysteine and homocysteic acid on glutamate receptors on rat lymphocytes

“…Disturbances in HC metabolism are followed by an increase in its concentration to 50-200 µM or higher [9]. Hyperhomocysteinemia increases the risk of atherosclerosis and myocardial infarction [11] and is a potent independent factor in the development of dementia and Alzheimer's disease [13].Under conditions of hyperhomocysteinemia the cells are exposed to neurotoxic influences. Disturbed metabolism of excitatory neurotransmitters (e.g., glutamate) causes the excitotoxic effects associated with increased intracellular level of reactive oxygen species (ROS) and oxidative damage to tissues.…”

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

“…Activation of these receptors by homocysteine produces cellular proliferation, suggesting that these receptors mediate the intimal hyperplasia found in hyperhomocysteinemia (31). Activation of NMDA receptors by homocysteine produces cellular proliferation, increased expression of matrix metalloproteinase-9, and interleukin-1β, decreased vascular production of nitric oxide, and increased production of the nitric oxide inhibitor ADMA in cultured rat smooth muscle cells (248). These results suggest that endothelial dysfunction is induced by homocysteine through activation of NMDA receptors.…”