12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1 Alison Sexton, Michelle McDonald, Cecile Cayla, Chris Thiemermann and Amrita Ahluwalia 1 William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK 1 Correspondence: Clinical Pharmacology, William Harvey Research Institute, Charterhouse Sq., London EC1M 6BQ, UK. E-mail: a.ahluwalia@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 (∼EC 50 s of 6 x 10 –19 and 1 x 10 –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
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12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1
Sexton, Alison; McDonald, Michelle; Cayla, Cecile; Thiemermann, Chris; Ahluwalia, Amrita
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, Volume 21 (11): 2695
Fed of American Socs for Experimental Biology – Sep 1, 2007
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