title: Sympathetic denervation of peri-infarct myocardium requires the p75 neurotrophin receptor.
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 (p75(NTR)) in sympathetic neurons causes axon degeneration. We used mice that lack p75(NTR) to test the hypothesis that activation of p75(NTR) causes peri-infarct sympathetic denervation after cardiac ischemia-reperfusion. Wild type hearts exhibited sympathetic denervation adjacent to the infarct 24h and 3 days after ischemia-reperfusion, but no peri-infarct sympathetic denervation occurred in p75(NTR)-/- mice. Sympathetic hyperinnervation was found in the distal peri-infarct myocardium in both genotypes 3 days after MI, and hyperinnervation was increased in the p75(NTR)-/- mice. By 7 days after ischemia-reperfusion, cardiac sympathetic innervation density returned back to sham-operated levels in both genotypes, indicating that axonal pruning did not require p75(NTR). 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 p75(NTR) 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 p75(NTR) ligands are elevated in the left ventricle after ischemia-reperfusion where they may stimulate p75(NTR)-dependent denervation of peri-infarct myocardium. In contrast, NGF-induced sympathetic hyperinnervation in the distal peri-infarct ventricle is attenuated by p75(NTR).
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd. Portland, OR 97239, USA.
authors.forename: Christina U
authors.initials: CU
authors.lastname: Lorentz
authors.forename: Diana C
authors.initials: DC
authors.lastname: Parrish
authors.forename: Eric N
authors.initials: EN
authors.lastname: Alston
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pellegrino
authors.forename: William R
authors.initials: WR
authors.lastname: Woodward
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Beth A
authors.initials: BA
authors.lastname: Habecker
mesh_terms: D000818:Animals; D005260:Female; D006335:Heart Injuries / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000294:innervation* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency*; D013562:Sympathectomy / Q000379:methods*
chemical_list: D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse
keywords: 123I-MIBG; Axon degeneration; BDNF; Brain-derived neurotrophic factor; HA; Ischemia–reperfusion; LAD; MI; NE; NGF; Pruning; Regeneration; SCG; TH; TrkA; brain-derived neurotrophic factor; hemagglutinin; iodine-123 meta-iodobenzylguanidine; left anterior descending coronary artery; myocardial infarction; nerve growth factor; norepinephrine; p75 neurotrophin receptor; p75(NTR); superior cervical ganglia; tropomyosin-related receptor kinase A; tyrosine hydroxylase