title: Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway.
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.
authors.affiliation: Department of Cardiovascular Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lu
authors.forename: Yih-Sharng
authors.initials: YS
authors.lastname: Chen
authors.forename: Ho-Shiang
authors.initials: HS
authors.lastname: Huang
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Ma
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D002109:Caffeic Acids / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D000860:Hypoxia / Q000201:enzymology*; D066298:In Vitro Techniques; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D017208:Rats, Wistar; D012508:Sarcolemma / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002109:Caffeic Acids; D044950:Flavanones; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D011493:Protein Kinase C; C071423:capsazepine; D002211:Capsaicin