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