Lipoxygenase-derived eicosanoids in myocardial ischaemia-reperfusion injury: the role of sensory C-fibres and TRPV1
It is well established that the 12-lipoxygenase (12-LOX) pathway of arachidonic acid (AA) metabolism is stimulated within the myocardium by episodes of ischaemia, and there is considerable evidence showing that eicosanoids derived via this pathway protect against the damaging effects of myocardial ischaemia-reperfusion (I/R) injury. Recent evidence suggests that transient receptor potential vanilloid receptor 1 (TRPV1), expressed on sensory C-fibres, may play an important protective role against myocardial I/R injury; and in neurones, the 12-LOX metabolite of AA 12(S)-hydroperoxyeicosatetraenoic acid [12(S)-HpETE], has been proposed as an endogenous ligand for TRPV1. However, whether 12(S)-HpETE underlies TRPV1 channel activation during myocardial I/R is unknown. Treatment of isolated Langendorff rat hearts with 12-LOX/AA significantly attenuated I/R injury (~40% inhibition of infarct size), an effect reversed by the 12-LOX inhibitor baicalein or by chemical desensitisation of local C-fibre afferents in vivo using capsaicin. Both 12(S)-HpETE and AA caused dose-dependent coronary vasodilatation (~pEC50s of 18.2 and 6.9, respectively) that was profoundly suppressed by the TRPV1 antagonist capsazepine, or in hearts of TRPV1 knockout mice compared to wild-type mice, or by treatment with the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37. I/R in vitro reduced expression of myocardial TRPV1 protein, whereas in vivo, TRPV1 protein expression in the heart and dorsal root ganglia (DRG) increased, and DRG TRPV1 messenger ribonucleic acid levels decreased – suggesting that whilst TRPV1 protein may be down-regulated during I/R in vitro, when neurones innvervating the heart are associated with their cell bodies, TRPV1 expression may be increased, possibly under the control of neurotrophic factors. Together, the findings from this thesis identify a novel 12-LOX/AA/TRPV1 pathway activated and up-regulated during myocardial I/R injury, providing an endogenous damage-limiting mechanism – the targeting of which may prove useful in treating myocardial infarction or protecting against I/R injury associated with common surgical procedures including cardiac transplantation.
- Theses