Sympathetic denervation of peri-infarct myocardium requires the p75 neurotrophin receptor

Christina U. Lorentz, Diana C. Parrish, Eric N. Alston, Michael J. Pellegrino, William Woodward, Barbara L. Hempstead, Beth Habecker

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Development of cardiac sympathetic heterogeneity after myocardial infarction contributes to ventricular arrhythmias and sudden cardiac death. Regions of sympathetic hyperinnervation and denervation appear in the viable myocardium beyond the infarcted area. While elevated nerve growth factor (NGF) is implicated in sympathetic hyperinnervation, the mechanisms underlying denervation are unknown. Recent studies show that selective activation of the p75 neurotrophin receptor (p75NTR) in sympathetic neurons causes axon degeneration. We used mice that lack p75NTR to test the hypothesis that activation of p75NTR causes peri-infarct sympathetic denervation after cardiac ischemia-reperfusion. Wild type hearts exhibited sympathetic denervation adjacent to the infarct 24h and 3days after ischemia-reperfusion, but no peri-infarct sympathetic denervation occurred in p75NTR-/- mice. Sympathetic hyperinnervation was found in the distal peri-infarct myocardium in both genotypes 3days after MI, and hyperinnervation was increased in the p75NTR-/- mice. By 7days after ischemia-reperfusion, cardiac sympathetic innervation density returned back to sham-operated levels in both genotypes, indicating that axonal pruning did not require p75NTR. Prior studies revealed that proNGF is elevated in the damaged left ventricle after ischemia-reperfusion, as is mRNA encoding brain-derived neurotrophic factor (BDNF). ProNGF and BDNF preferentially bind p75NTR rather than TrkA on sympathetic neurons. Immunohistochemistry using Bdnf-HA mice confirmed the presence of BDNF or proBDNF in the infarct after ischemia-reperfusion. Thus, at least two p75NTR ligands are elevated in the left ventricle after ischemia-reperfusion where they may stimulate p75NTR-dependent denervation of peri-infarct myocardium. In contrast, NGF-induced sympathetic hyperinnervation in the distal peri-infarct ventricle is attenuated by p75NTR.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalExperimental Neurology
Volume249
DOIs
StatePublished - Nov 2013

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Keywords

  • Axon degeneration
  • Brain-derived neurotrophic factor
  • Ischemia-reperfusion
  • Pruning
  • Regeneration

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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