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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.

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.

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Acknowledgments

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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Authors and Affiliations

  1. Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

    Shintaro Nakano, Takako Hishiki & Makoto Suematsu

  2. Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Shibakoen 1-5-30, Minato-ku, Tokyo, 105-8512, Japan

    Isao Ishii & Shotaro Kamata

  3. Department of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan

    Ken Shinmura & Kayoko Tamaki

  4. Suematsu Gas Biology Project, ERATO, JST, Tokyo, Japan

    Kayoko Tamaki, Takako Hishiki, Noriyuki Akahoshi & Makoto Suematsu

  5. Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Tomoaki Ida & Takaaki Akaike

  6. MS Business Unit, Shimadzu Corporation, Kyoto, Japan

    Tsuyoshi Nakanishi

  7. Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki, Japan

    Yoshito Kumagai

  8. Department of Cardiology, Keio University School of Medicine, Tokyo, Japan

    Keiichi Fukuda & Motoaki Sano

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  1. Shintaro Nakano
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  2. Isao Ishii
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  3. Ken Shinmura
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Correspondence to Isao Ishii.

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Nakano, S., Ishii, I., Shinmura, K. et al. Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions. J Mol Med 93, 879–889 (2015). https://doi.org/10.1007/s00109-015-1271-5

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  • DOI: https://doi.org/10.1007/s00109-015-1271-5

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