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H2 Mediates Cardioprotection Via Involvements of KATP Channels and Permeability Transition Pores of Mitochondria in Dogs

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Abstract

Purpose

Inhalation of hydrogen (H2) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H2 gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mKATP) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H2 gas in canine hearts.

Methods

The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H2 or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mKATP blocker), or atractyloside (Atr; a mPTP opener).

Results

Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H2 gas inhalation reduced infarct size normalized by risk area (20.6 ± 2.8% vs. control gas 44.0 ± 2.0%; p < 0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H2 gas (42.0 ± 2.2% with 5-HD and 45.1 ± 2.7% with Atr; both p < 0.001 vs. H2 group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H2 was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway.

Conclusions

Inhalation of H2 gas reduces infarct size in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mPTP. H2 gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.

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Acknowledgements

This work was supported by the Grants-in-aid from the Ministry of Health, Labor, and Welfare-Japan (H23-Nanchi-Ippan-22 to M.K.) and Grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology-Japan (21390251 to M.K.) and Grants from the Japan Heart Foundation and Grants from the Japan Cardiovascular Research Foundation. The authors thank Akiko Ogai for her technical assistance; Hatsue Ishibashi-Ueda for advice about TUNEL staining and Imai Nobuyoshi for his technical assistance with TUNEL staining; Kyoko Shioya for her assistance with animal care; Toshiyasu Asahara and Masaharu Onogi (TAIYO NIPPON SANSO Co.) for providing information about hydrogen.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita 565-8565, Osaka, Japan

    Akemi Yoshida, Hideyuki Sasaki, Satoru Yamazaki, Masanori Asakura & Masafumi Kitakaze

  2. Department of Cardiovascular Science and Technology, Kyoto Prefectural University of Medicine, Suita 565-8565, Osaka, Japan

    Hiroshi Asanuma

  3. Department of Structural Analysis, National Cerebral and Cardiovascular Research Center, Suita, Japan

    Akemi Yoshida & Naoki Mochizuki

  4. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan

    Shoji Sanada, Yoshihiro Asano, Tetsuo Minamino & Seiji Takashima

  5. Department of Physiological Science, Tokai University Graduate School of Medicine, Isehara, Japan

    Yoshiro Shinozaki & Hidezo Mori

  6. Department of Cardiac Physiology, National Cerebral and Cardiovascular Research Center, Suita, Japan

    Akito Shimouchi

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

    Motoaki Sano

  8. Department of Cardiovascular Dynamics, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan

    Masaru Sugimachi

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  1. Akemi Yoshida
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Correspondence to Masafumi Kitakaze.

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Yoshida, A., Asanuma, H., Sasaki, H. et al. H2 Mediates Cardioprotection Via Involvements of KATP Channels and Permeability Transition Pores of Mitochondria in Dogs. Cardiovasc Drugs Ther 26, 217–226 (2012). https://doi.org/10.1007/s10557-012-6381-5

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