Hyperhomocysteinemia, a cardiac metabolic disease role of nitric oxide and the p22phox subunit of NADPH oxidase

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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 O 2 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 p22phox subunit of NADPH oxidase. Western blots with plasma membrane-enriched fractions of cell lysate detected elevated levels of p22phox, p67phox, and rac-1, which indicates increased oxidase assembly. Finally, mice lacking a functional gp91phox 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.

Original languageEnglish
Pages (from-to)2112-2118
Number of pages7
Issue number16
StatePublished - 26 Apr 2005
Externally publishedYes


  • Free radicals
  • Homocysteine
  • Nitric oxide


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