Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd. Portland, OR 97239, USA.
Exp Neurol. 2013 Nov;249:111-9. doi: 10.1016/j.expneurol.2013.08.015. Epub 2013 Sep 3.
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).
梗死后心脏交感神经异质性的发展导致室性心律失常和心脏性猝死。在梗死区域以外的存活心肌中出现交感神经过度支配和去神经支配区域。虽然升高的神经生长因子 (NGF) 与交感神经过度支配有关，但去神经支配的机制尚不清楚。最近的研究表明，交感神经元中 p75 神经生长因子受体 (p75(NTR)) 的选择性激活导致轴突退化。我们使用缺乏 p75(NTR) 的小鼠来检验假设，即心脏缺血再灌注后 p75(NTR) 的激活导致梗死周围交感神经去神经支配。野生型心脏在缺血再灌注后 24 小时和 3 天表现出梗死旁交感神经去神经支配，但 p75(NTR)-/- 小鼠没有发生梗死周围交感神经去神经支配。在两种基因型中，在 MI 后 3 天都发现了远侧梗死周围心肌的交感神经过度支配，并且 p75(NTR)-/- 小鼠的过度支配增加了。在缺血再灌注后 7 天，两种基因型的心脏交感神经支配密度均恢复到假手术水平，这表明轴突修剪不需要 p75(NTR)。先前的研究表明，缺血再灌注后受损的左心室中 proNGF 升高，脑源性神经营养因子 (BDNF) 的 mRNA 编码也升高。proNGF 和 BDNF 优先与交感神经元上的 p75(NTR)而不是 TrkA 结合。使用 Bdnf-HA 小鼠进行免疫组织化学证实，缺血再灌注后在梗死中存在 BDNF 或 proBDNF。因此，至少两种 p75(NTR)配体在缺血再灌注后的左心室中升高，它们可能刺激梗死周围心肌的 p75(NTR)依赖性去神经支配。相比之下，NGF 诱导的远侧梗死周围心室的交感神经过度支配被 p75(NTR)减弱。
