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12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1

William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK

¹Correspondence: Clinical Pharmacology, William Harvey Research Institute, Charterhouse Sq., London EC1M 6BQ, UK. E-mail: a.ahluwalia{at}qmul.ac.uk

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 (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 (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, A., McDonald, M., Cayla, C., Thiemermann, C., Ahluwalia, A. 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1.

Key Words: coronary vasodilation • channel activation • capsaicin receptor