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Hypoxic preconditioning protects rat hearts against ischemia–reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway

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Abstract

Hypoxic preconditioning (HPC) protects rat hearts against ischemia–reperfusion (IR) injury. However, the role of transient receptor potential vanilloid 1 (TRPV1) in HPC-mediated cardioprotection remains unknown. TRPV1 is activated by endovanilloid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which is synthesized by arachidonate 12-lipoxygenase (ALOX12). Therefore, we examined whether HPC protects the myocardium against IR via the ALOX12/TRPV1 pathway. Compared to hearts of rats kept in room air, the hearts of rats kept in air with 10 % oxygen for 4 weeks had better post-ischemic recovery and less tissue damage when subjected to 30-min global ischemia and 4-h reflow in a Langendorff apparatus. Capsazepine, a specific TRPV1 blocker, administered 5 min before reperfusion markedly attenuated the effects of HPC, confirming that TRPV1 is a downstream effector in HPC-mediated cardioprotection. HPC resulted in the upregulation of ALOX12 and myocardial 12(S)-HETE, and prevented IR-induced 12(S)-HETE reduction. In addition, sarcolemmal ALOX12 expression in HPC hearts mainly co-localized with TRPV1 expression. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein abrogated the effects of HPC, baicalein also decreased 12(S)-HETE expression. Mimicking HPC by given 12(S)-HETE or capsaicin to baicalien-treated hearts enhanced cardiac recovery during reperfusion. The cardiac protein kinase C (PKC) isoforms α, δ, ε, and ζ were preferentially expressed in the sarcolemmal membrane of HPC-treated hearts, indicating their high intrinsic activation state. Capsazepine or co-treatment with baicalein attenuated translocation of PKCα, PKCδ and PKCε, but not that of PKCζ. We conclude that HPC reduces heart susceptibly to IR via ALOX12/TRPV1/PKC pathway, as shown by increased 12(S)-HETE expression in HPC hearts.

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Acknowledgments

This study was supported by the Shin Kong Wu Ho-Su Memorial Hospital (99SKH-FJU-09, 100SKH-FJU-01) and the National Science Council (101-2314-B-030-002-MY3).

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiovascular Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    Ming-Jen Lu

  2. Department of Cardiovascular Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Yih-Sharng Chen

  3. Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan

    Ho-Shiang Huang

  4. School of Medicine, Fu-Jen Catholic University, 510 Chungcheng Road, Hsinchuang District, New Taipei City, 24205, Taiwan

    Ming-Chieh Ma

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  1. Ming-Jen Lu
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Correspondence to Ming-Chieh Ma.

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M. J. Lu and Y. S. Chen equally contributed in this work.

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Lu, MJ., Chen, YS., Huang, HS. et al. Hypoxic preconditioning protects rat hearts against ischemia–reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. Basic Res Cardiol 109, 414 (2014). https://doi.org/10.1007/s00395-014-0414-0

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  • DOI: https://doi.org/10.1007/s00395-014-0414-0

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