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(Circulation. 2005;111:2112-2118.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Hyperhomocysteinemia, a Cardiac Metabolic Disease

Role of Nitric Oxide and the p22^phox Subunit of NADPH Oxidase

Justin S. Becker; Alexandra Adler; Aaron Schneeberger; Harer Huang, MD; Zipping Wang, MS; Erin Walsh, MS; Akos Koller, MD, PhD; Thomas H. Hintze, PhD

From the Department of Physiology, New York Medical College, Valhalla, NY.

Correspondence to Professor Thomas H. Hintze, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}NYMC.edu

Received July 9, 2004; revision received November 15, 2004; accepted November 18, 2004.

Background— Hyperhomocysteinemia (HHcy) is a reliable indicator of cardiovascular disease, in part because of the production of superoxide and scavenging of nitric oxide (NO). The present study assessed the impact of HHcy on the NO-dependent control of cardiac O₂ consumption and examined enzymatic sources of superoxide.

Methods and Results— Rats and mice were fed methionine in drinking water for 5 to 9 weeks to increase plasma homocysteine, a process that did not cause significant changes in hemodynamic function. The ability of the NO agonists bradykinin and carbachol to reduce myocardial O₂ consumption in vitro was impaired by 40% in methionine-fed rats, and this impairment was proportional to their individual plasma homocysteine concentration. However, responses were restored in the presence of ascorbic acid, tempol, and apocynin, which inhibits NADPH oxidase assembly. Western blots showed no difference in Cu/Zn or Mn superoxide dismutase, endothelial NO synthase, or inducible NO synthase protein, but HHcy caused a 100% increase in the p22^phox subunit of NADPH oxidase. Western blots with plasma membrane–enriched fractions of cell lysate detected elevated levels of p22^phox, p67^phox, and rac-1, which indicates increased oxidase assembly. Finally, mice lacking a functional gp91^phox subunit of NADPH oxidase demonstrated normal NO-dependent regulation of myocardial O₂ consumption after methionine feeding.

Conclusions— In HHcy, superoxide produced by NADPH oxidase reduces the ability of NO to regulate mitochondrial function in the myocardium. The severity of this effect is proportional to the increase in homocysteine.

Key Words: homocysteine • nitric oxide • free radicals

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