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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative
Nobuhiro Suematsu1, Caroline Ojaimi, Shintaro Kinugawa
1Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Insights
Hyperhomocysteinemia (HHcy) impairs heart function by increasing oxidative stress and altering myocardial metabolism. Ascorbic acid and other antioxidants can restore normal cardiac function, suggesting new therapeutic targets for related heart diseases.
Area of Science:
- Cardiovascular Physiology
- Metabolic Research
- Oxidative Stress Biology
Background:
- Hyperhomocysteinemia (HHcy) is linked to vascular disease and oxidative stress.
- The specific impact of HHcy on cardiac function and myocardial metabolism remains largely uncharacterized.
Purpose of the Study:
- To investigate the effects of HHcy on cardiac function, NO bioavailability, and myocardial substrate utilization in a canine model.
- To explore the role of oxidative stress in HHcy-induced cardiac alterations.
Main Methods:
- Intravenous infusion of L-homocysteine and dietary methionine to induce acute and chronic HHcy in conscious dogs.
- Assessment of hemodynamics, NO-dependent coronary vasodilation, and myocardial substrate uptake (glucose, lactate, free fatty acids).
- In vitro studies on myocardial oxygen consumption and Western blot analysis for key proteins (Nox2, eNOS, SOD-1).
Main Results:
- HHcy did not significantly alter hemodynamics but reduced NO-dependent vasodilation, which was restored by antioxidants.
- Cardiac glucose and lactate uptake increased, while free fatty acid uptake decreased under HHcy.
- HHcy decreased myocardial oxygen consumption, an effect reversed by antioxidants, and increased Nox2 while decreasing eNOS and SOD-1 expression.
Conclusions:
- HHcy directly alters cardiac substrate utilization and metabolism by reducing NO bioavailability via superoxide generation, independent of hemodynamic changes.
- These findings highlight the critical role of oxidative stress in HHcy-related cardiac dysfunction and suggest evaluating cardiac metabolism alterations in disease progression.
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.
Methods And 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.
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