Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress.
BACKGROUND
Hyperhomocysteinemia (HHcy) has been considered a vascular disease associated with increased levels of oxidative stress that results in scavenging of NO. However, little is known of the impact of HHcy on cardiac function and especially myocardial metabolism.


RESULTS
L-Homocysteine was intravenously infused into conscious dogs, and the dogs were fed methionine to increase plasma homocysteine to 10 micromol/L for acute and 24 micromol/L for chronic HHcy. There was no significant change in hemodynamics with HHcy. Veratrine-induced, NO-dependent, coronary vasodilation (Bezold-Jarisch reflex) was reduced by 32% but was restored by simultaneous intravenous infusion of ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy significantly decreased bradykinin- or carbachol-induced reduction of myocardial oxygen consumption in vitro, and this effect was completely restored by coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis indicated an increase in Nox2 (82%) and a reduction in endothelial nitric oxide synthase (39%), phospho-endothelial nitric oxide synthase (39%), and superoxide dismutase-1 (45%). Microarray analysis of gene expression in heart tissue from chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize glucose.


CONCLUSIONS
HHcy directly modulates substrate use by the heart independent of changes in hemodynamics or ventricular function by reducing NO bioavailability through the generation of superoxide. The progression of cardiac or coronary heart disease associated with HHcy should be evaluated in light of the impact of alterations in the regulation of cardiac metabolism and substrate use.
Suematsu
Nobuhiro
N
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Ojaimi
Caroline
C
Kinugawa
Shintaro
S
Wang
Zipping
Z
Xu
Xiaobin
X
Koller
Akos
A
Recchia
Fabio A
FA
Hintze
Thomas H
TH
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000097:blood*; D008297:Male; D009569:Nitric Oxide / Q000097:blood*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology
D006710:Homocysteine; D009569:Nitric Oxide