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

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          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.

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          Author and article information

          Journal
          J. Mol. Med.
          Journal of molecular medicine (Berlin, Germany)
          Springer Nature
          1432-1440
          0946-2716
          Aug 2015
          : 93
          : 8
          Affiliations
          [1 ] Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
          Article
          10.1007/s00109-015-1271-5
          10.1007/s00109-015-1271-5
          25740079
          736c19b8-383c-4ea8-a3df-711b29bb3fa2
          History

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