Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans

Hiroaki Shimokawa, Keiko Morikawa

Research output: Contribution to journalReview articlepeer-review

112 Citations (Scopus)


The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating substances, including vasodilator prostaglandins, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Since the first report for the existence of EDHF, several substances/mechanisms have been proposed for the nature of EDHF, including epoxyeicosatrienoic acids (metabolites of arachidonic P450 epoxygenase pathway), K ions, and electrical communications through myoendothelial gap junctions. We have recently demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in mouse and human mesenteric arteries and in porcine coronary microvessels. For the synthesis of H 2O2 as an EDHF, endothelial Cu,Zn-superoxide dismutase plays an important role in mesenteric arteries of mice and humans. We also have demonstrated that EDHF-mediated responses are attenuated by several arteriosclerotic risk factors, including diabetes mellitus and hyperlipidemia and their combination in particular. Recent studies have indicated that endothelium-derived H2O2 plays an important protective role in coronary autoregulation and myocardial ischemia/reperfusion injury in vivo. Indeed, our H2O2/EDHF theory demonstrates that endothelium-derived H2O2, another reactive oxygen species in addition to NO, plays an important role as a redox signaling molecule to cause vasodilatation as well as cardioprotection. In this review, we summarize our knowledge on H2O2/EDHF regarding its identification, mechanisms of synthesis, and clinical implications.

Original languageEnglish
Pages (from-to)725-732
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Issue number5
Publication statusPublished - 2005 Nov
Externally publishedYes


  • Endothelium
  • Endothelium-derived hyperpolarizing factor
  • Hydrogen peroxide
  • Membrane potential

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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