Proneurotrophins mediate peri‐infarct sympathetic denervation following myocardial infarction

Abstract

Altered sympathetic innervation of the heart is a major contributor to arrythmogenesis following myocardial infarction (MI). Changes to the innervation include denervation of peri‐infarct myocardium. Activation of the p75 neurotrophin receptor leads to axon degeneration, and we asked if the denervation of peri‐infarct myocardium was caused by p75 activation. Sympathetic innervation density was quantified by tyrosine hydroxylase immunohistochemistry in 12–18 week old p75 −/− and wild‐type control mice (C57Bl6/J) that were subjected to sham or ischemia‐reperfusion surgery. By 24 hours post‐MI, the peri‐infarct zone was largely denervated in wild‐type mice, and this denervation persisted up to 3 days. In contrast, peri‐infarct denervation was absent in p75 −/− mice. Both pro‐ and mature neurotrophins bind the p75 neurotrophin receptor. We quantified the levels of mature and proneurotrophins in the left ventricle of wild‐type mice 24 hours following MI by western blotting. Pro‐brain derived neurotrophic factor (proBDNF) was elevated in the infarcted left ventricle compared to sham‐operated controls, while mature BDNF was not detected. Both pro‐ and mature nerve growth factor (NGF) were detected in the infarcted left ventricle, with proNGF being the more abundant species. Application of proBDNF‐conditioned media to sympathetic ganglia explants resulted in reduced axon length. These data suggest a role for proneurotrophins in acute peri‐infarct sympathetic denervation of the left ventricle.