Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions

Shintaro Nakano, Isao Ishii, Ken Shinmura, Kayoko Tamaki, Takako Hishiki, Noriyuki Akahoshi, Tomoaki Ida, Tsuyoshi Nakanishi, Shotaro Kamata, Yoshito Kumagai, Takaaki Akaike, Keiichi Fukuda, Motoaki Sano, Makoto Suematsu

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


Abstract: Elevated plasma homocysteine levels are considered an independent risk factor for cardiovascular diseases. Experimental evidence has shown that hydrogen sulfide anion (HS) protects the myocardium from ischemia/reperfusion (IR) injury. Both homocysteine levels and endogenous HS production are mainly regulated by two transsulfuration enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). We hypothesized that the transsulfuration pathway plays essential roles in the development of cardiac adaptive responses against ischemia, and investigated the roles of homocysteine, HS, and transsulfuration enzymes in fasting-induced cardioprotection against IR injury utilizing hyperhomocysteinemic Cbs−/− and Cth−/− mice. Langendorff-perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. Two-day fasting ameliorated left ventricular dysfunction after reperfusion via propargylglycine- and glibenclamide-sensitive pathways in wild-type mice but not in Cbs−/− or Cth−/− mice, although fasting induced cardiac expression of several Nrf2 target antioxidant genes in both wild-type and Cth−/− mice. Intraperitoneal administration of sodium hydrosulfide (a HS donor) at 24 h prior to IR improved myocardial recovery in wild-type mice but not in Cth−/− or high-methionine-diet-fed (thus intermediately hyperhomocysteinemic) wild-type mice. Quantitative analysis of reactive sulfur species using monobromobimane derivatization methods revealed that homocysteine efficiently captures HS to form homocysteine persulfide in the hearts as well as in the in vitro reactions. Here we propose a novel molecular and pathophysiological basis for hyperhomocysteinemia; excessive circulatory homocysteine interferes with HS-related cardioprotection against IR injury by capturing endogenous HS to form homocysteine persulfide. Key Message: Two-day fasting of mice ameliorates ischemia/reperfusion injury in Langendorff hearts.H2S-producing enzymes, CBS and CTH, are essential in fasting-induced cardioprotection.Administration of a H2S donor (NaHS) confers cardioprotection against IR injury.NaHS effects are absent in Cth−/−, Cbs−/−, and dietary hyperhomocysteinemic mice.Homocysteine captures cardioprotective HS to form homocysteine persulfide.

Original languageEnglish
Pages (from-to)879-889
Number of pages11
JournalJournal of Molecular Medicine
Issue number8
Publication statusPublished - 2015 Aug 25


  • Fasting
  • Homocysteine persulfide
  • Hydrogen sulfide anion (HS)
  • Ischemia/reperfusion injury
  • Preconditioning
  • Transsulfuration

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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