12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1.
Recent evidence implicates the neuronal transient receptor potential vanilloid receptor 1 (TRPV1), expressed on sensory C-fibers, as playing an important endogenous protective role in limiting the damaging effects of myocardial I/R injury. In neurons the 12-lipoxygenase (12-LOX) arachidonic acid (AA) metabolite, 12(S)-HpETE, has been proposed as the endogenous ligand for TRPV1. However, whether 12(S)-HpETE underlies TRPV1 channel activation during I/R is unknown. Treatment of isolated Langendorff rat hearts with a 12-LOX/AA cocktail significantly attenuated I/R injury (approximately 40% inhibition of infarct size), an effect reversed by the 12-LOX inhibitor baicalein or after chemical desensitization of local sensory C-fiber afferents using capsaicin. Both 12(S)-HpETE and AA caused dose-dependent coronary vasodilatation (approximately EC50s of 6x10(-19) and 1x10(-7), respectively) that was profoundly suppressed by the TRPV1 antagonist capsazepine, in hearts of TRPV1 knockout mice compared with wild-type mice, or by treatment with a CGRP antagonist. In addition, I/R itself stimulates up-regulation of TRPV1 expression in both the cell bodies located within the dorsal root ganglia and locally within the myocardium. Together, our data identify a novel 12-LOX/AA/TRPV1 pathway activated and up-regulated during I/R injury, providing an endogenous damage-limiting mechanism whose targeting may prove useful in treating myocardial infarction.
Sexton
Alison
A
William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK.
McDonald
Michelle
M
Cayla
Cecile
C
Thiemermann
Chris
C
Ahluwalia
Amrita
A
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015777:Eicosanoids / Q000494:pharmacology*; D006321:Heart / Q000502:physiology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D015777:Eicosanoids; D015289:Leukotrienes; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D016718:Arachidonic Acid; C021201:12-HPETE; D001092:Arachidonate 12-Lipoxygenase; D015740:Calcitonin Gene-Related Peptide