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

• Published in: Basic research in cardiology Vol. 109; no. 4; p. 414
• Main Authors: Lu, Ming-Jen, Chen, Yih-Sharng, Huang, Ho-Shiang, Ma, Ming-Chieh
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2014; Springer Nature B.V
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - metabolism; Animals; Arachidonate 12-Lipoxygenase - metabolism; Caffeic Acids - pharmacology; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cardiology; Flavanones - pharmacology; Hypoxia - enzymology; In Vitro Techniques; Isoenzymes; Lipoxygenase Inhibitors - pharmacology; Male; Medicine; Medicine & Public Health; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - prevention & control; Myocardium - enzymology; Original Contribution; Protein Kinase C - metabolism; Protein Transport; Rats, Wistar; Sarcolemma - enzymology; Signal Transduction - drug effects; Time Factors; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; Hypoxic preconditioning; Transient receptor potential vanilloid 1; Protein kinase C; Cardioprotection; Arachidonate 12-lipoxygenase
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-014-0414-0

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.