Abstract 779: Hyperhomocysteinemia Alters Cardiac Substrate Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress
The purpose of this study was to evaluate the potential impact of HHcy on cardiac function, oxygen consumption, and myocardial metabolism with special reference to the production of superoxide and scavenging of nitric oxide (NO). L-Homocysteine was intravenously infused into conscious adult male dogs, and then they were fed methionine. Plasma homocysteine (Hcy) concentration was significantly increased to 10.1±1.8μM by the infusion and 24.3±9.6μM by the feeding compared to control (4.4±0.2μM) (P<0.01, n=10 each). There was no significant change in hemodynamics between control and HHcy. Veratrine induced NO dependent coronary vasodilation was reduced by 32% which was completely restored by simultaneous intravenous infusion of ascorbic acid or apocyinin (P<0.05, n=5 each). The acute Hcy significantly increased glucose uptake (1.5±0.7 to 7.5±1.6 μmol/min, P<0.01, n=7) and decreased FFA uptake (7.4±1.1 to 3.9±1.1 μmol/min, P<0.05, n=6). Similarly, the chronic HHcy increased both glucose uptake (2.9±0.5 to 9.5±0.9 μmol/min, P<0.01, n=7) and lactate uptake (3.9±2.3 to 16.0±4.1 μmol/min, P<0.05, n=7) and decreased FFA uptake (7.7±0.8 to 1.9±1.0 μmol/min, P<0.01, n=5). Myocardial oxygen consumption (MVO2) of LV tissue from chronic HHcy was also measured in vitro in response to bradykinin (BK) and carbachol. BK and carbacol induced reduction of MVO2 was significantly decreased by HHcy which was completely recovered with coincubation with ascorbic acid, tempol, or apocynin (P<0.05, n=6 each). Western blotting of LV tissues from HHcy showed an increased expression of gp91phox (82.0%) and decreased expression of eNOS (−39.6%), phospho-eNOS (−39.2%), SOD-1 (−45.0%), and phospho-p47phox (−73.4%) (P<0.01, n=6 each). Alterations of some cardiac gene expression including both functional and metabolic gene from chronic HHcy was also observed by microarray analysis. In conclusion, HHcy directly modulates the substrate use of heart without any change of hemodynamics or ventricular function by inhibiting NO bioavailability through the generation of superoxide. Evaluation of the progression of cardiac or coronary heart disease associated with HHcy should include the impact of alterations in the regulation of cardiac metabolism and substrate use.