Homocysteine (Hcy) causes cerebrovascular dysfunction by inducing oxidative stress. However, to date, there are no strategies to prevent Hcy-induced oxidative damage. Hcy is an H 2 S precursor formed from methionine (Met) metabolism. We aimed to investigate whether H 2 S ameliorated Met-induced oxidative stress in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to Met treatment in the presence or absence of NaHS (donor of H 2 S). Met-induced cell toxicity increased the levels of free radicals in a concentration-dependent manner. Met increased NADPH-oxidase-4 (NOX-4) expression and mitigated thioredxion-1(Trx-1) expression. Pretreatment of bEnd3 with NaHS (0.05 mM) attenuated the production of free radicals in the presence of Met and protected the cells from oxidative damage. Furthermore, NaHS enhanced inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), N -nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzymes levels induced by Met. In conclusion, the administration of H 2 S protected the cells from oxidative stress induced by hyperhomocysteinemia (HHcy), which suggested that NaHS/H 2 S may have therapeutic potential against Met-induced oxidative stress. Antioxid. Redox Signal. 11,[25][26][27][28][29][30][31][32][33]

WE, Tseng MT, Tyagi SC. Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia. myocyte N-methyl-D-aspartate receptor-1 (NMDA-R1) activation induces mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) induction is a negative regulator of mitochondrial function. Elevated levels of homocysteine [hyperhomocysteinemia (HHCY)] activate latent MMPs and causes myocardial contractile abnormalities. HHCY is associated with mitochondrial dysfunction. We tested the hypothesis that HHCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction by agonizing NMDA-R1. The C57BL/6J mice were administered homocystinemia (1.8 g/l) in drinking water to induce HHCY. NMDA-R1 expression was detected by Western blot and confocal microscopy. Localization of MMP-9 in the mitochondria was determined using confocal microscopy. Ultrastructural analysis of the isolated myocyte was determined by electron microscopy. Mitochondrial permeability was measured by a decrease in light absorbance at 540 nm using the spectrophotometer. The effect of MK-801 (NMDA-R1 inhibitor), GM-6001 (MMP inhibitor), and cyclosporine A (MPT inhibitor) on myocyte contractility and calcium transients was evaluated using the IonOptix video edge track detection system and fura 2-AM. Our results demonstrate that HHCY activated the mtMMP-9 and caused MPT by agonizing NMDA-R1. A significant decrease in percent cell shortening, maximal rate of contraction (ϪdL/dt), and maximal rate of relaxation (ϩdL/dt) was observed in HHCY. The decay of calcium transient amplitude was faster in the wild type compared with HHCY. Furthermore, the HHCY-induced decrease in percent cell shortening, ϪdL/dt, and ϩdL/dt was attenuated in the mice treated with MK-801, GM-6001, and cyclosporin A. We conclude that HHCY activates mtMMP-9 and induces MPT, leading to myocyte mechanical dysfunction by agonizing NMDA-R1. myocyte; calcium; mitochondrial permeability; N-methyl-D-aspartate receptor-1; arrhythmogenesis THE PATHOPHYSIOLOGY of chronic heart failure (CHF) involves abnormalities in systolic and/or diastolic function and increases the propensity for reentry arrhythmias (30, 6). Continued elevation of cardiac sympathetic drive contributes to myocardial toxicity, leading to the decline in cardiac contractility (29). Recent observations suggest an increase in glutamatergic activity on sympathetic regulation, due to the upregulation of hypothalamic N-methyl-D-aspartate receptor-1 subunits (NMDA-R1) during CHF (16). Ischemia-and reperfusion-induced arrhythmias are sensitive to NMDA-R1 blockade (8).Hyperhomocysteinemia (HHCY) is a graded risk factor for CHF (12, 7) and for sudden cardiac death (SCD) resulting from coronary fibrous plaques (4, 1, 5). Homocysteinemia (HCY) induces interstitial cardiac fibrosis leading to systolic/diastolic dysfunction (13). The antagonist to the NMDA-R protects against HCY-induced oxidative damage in neurons (10) and protects against...

Atherosclerosis is an inflammatory process that involves activation of matrix metalloproteinases (MMPs); MMPs degrade collagen and allow for smooth-muscle cell migration within a vessel. Moreover, this begets an accumulation of other cellular material, resulting in occlusion of the vessel and ischemic events to tissues in need of nutrients. Homocysteine has been shown to activate MMPs via an increase in oxidative stress and acting as a signaling molecule on receptors like the peroxisome proliferator activated receptor-γ and N-methyl-D-aspartate receptor. Nitric oxide has been shown to be beneficial in some cases of deactivating MMPs. However, in other cases, it has been shown to be harmful. Further studies are warranted on the scenarios that are beneficial versus destructive. Hydrogen sulfide (H2S) has been shown to decrease MMP activities in all cases in the literature by acting as an antioxidant and vasodilator. Various MMP-knockout and gene-silencing models have been used to determine the function of the many different MMPs. This has allowed us to discern the role that each MMP has in promoting or alleviating pathological conditions. Furthermore, there has been some study into the MMP polymorphisms that exist in the population. The purpose of this review is to examine the role of MMPs and their polymorphisms on the development of atherosclerosis, with emphasis placed on pathways that involve nitric oxide, hydrogen sulfide, and homocysteine.

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Background/Aims: Sodium thiosulfate (STS) has been shown to be an antioxidant and calcium solubilizer, but the possible role of STS in dysfunctional ventricles remains unknown. Here, we assessed the effects of STS in the failing heart. Methods: Heart failure was created by an arteriovenous fistula (AVF). Mice were divided into 4 groups: sham, AVF, sham + STS, and AVF + STS. STS (3 mg/ml) was supplemented with drinking water for 6 weeks in the appropriate surgery groups after surgery. Results: M-mode echocardiograms showed ventricular contractile dysfunction with reduced aortic blood flow in AVF mice, whereas STS treatment prevented the decline in cardiac function. Ventricular collagen, MMP-2 and -9, and TIMP-1 were robustly increased with a decreasing trend in adenylate cyclase VI expression; however, STS supplementation reversed these effects in AVF mice. Among 2 enzymes that produce endogenous hydrogen sulfide (H₂S), cystathionine-γ-lyase (CSE) expression was attenuated in AVF mice with no changes in cystathionine-β-synthase (CBS) expression. In addition, reduced production of H₂S in AVF ventricular tissue was normalized with STS supplementation. Moreover, cardiac tissues were more responsive to H₂S when AVF mice were supplemented with STS compared to AVF alone. Conclusions: These results suggested that STS modulated cardiac dysfunction and the extracellular matrix, in part, by increasing ventricular H₂S generation.