Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions
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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.
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.
KeywordsFasting Homocysteine persulfide Hydrogen sulfide anion (HS−) Ischemia/reperfusion injury Transsulfuration Preconditioning
This study was supported by Grants-in-Aid for Scientific Research [25460072 and 25220103 to I.I., 25461116 to K.S., 24651265 to T.H.] and the Program for Strategic Research Foundation at Private Universities (2011–2015) to I.I. from the MEXT of Japan; Keio Univ. Special Grant-in-Aid for Innovative Collaborative Research Project to I.I.; and ERATO Suematsu Gas Biology Project to M.Su. from JST. M.Su. was the leader of CREST, JST for FY2014.
Conflict of interest
The authors have nothing to disclose.
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