Hyperhomocysteinemia Alters The Cardiac Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress

Abstract

Hyperhomocysteinemia (HHcy) has been considered a vascular disease which is associated with increased levels of reactive oxygen species resulting in scavenging of nitric oxide (NO). However, little is known of the impact on cardiac function and myocardial metabolism. L-Homocysteine was intravenously infused into conscious adult male dogs (titrated to give plasma homocysteine up to 10μM over 120 minutes). There was no change in any hemodynamic parameters between baseline and HHcy. Veratrine induced NO dependent coronary vasodilation (Bezold-Jarisch reflex) was reduced by 29% which was restored by simultaneous infusion of ascorbic acid. Myocardial substrate use was calculated as coronary sinus-arterial difference times coronary blood flow. Acute HHcy significantly increased glucose uptake (1.7±1.2 to 6.8±1.2 μmol/min) and decreased FFA uptake (6.0±1.6 to 3.1±1.0 μmol/min). Lactate uptake was also increased (3.9±3.0 to 11.2±6.1 μmol/min). Myocardial oxygen consumption (MVO2) of LV tissue from chronic HHcy dogs (fed with methionine for 2 weeks) was also measured in vitro in response to bradykinin (BK). BK-induced reduction in MVO2 was significantly decreased by HHcy and this effect was completely inhibited with coincubation with ascorbic acid, tempol, or apocynin. In conclusion, HHcy modulates the substrate use of heart by inhibiting NO bioavailability through the generation of superoxide. The progression of the disease associated with HHcy should also be evaluated based on alterations in the regulation of cardiac metabolism and substrate use. Supported by HL-PO1-43023 grant.