Recombinant Extracellular Domain (p75ECD) of the Neurotrophin Receptor p75 Attenuates Myocardial Ischemia–Reperfusion Injury by Inhibiting the p‐JNK/Caspase‐3 Signaling Pathway in Rat Microvascular Pericytes

Abstract

Background Pro‐NTs (precursor of neurotrophins) and their receptor p75 are potential targets for preventing microvascular dysfunction induced by myocardial ischemia–reperfusion injury (IRI). p75ECD (ectodomain of neurotrophin receptor p75) may physiologically produce neurocytoprotective effects by scavenging pro‐NTs. We therefore hypothesized that p75ECD may have a cardioprotective effect on IRI through microvascular mechanisms. Methods and Results Myocardial IRI was induced in Sprague‐Dawley rats by occluding the left main coronary arteries for 45 minutes before a subsequent relaxation. Compared with the ischemia–reperfusion group, an intravenous injection of p75ECD (3 mg/kg) 5 minutes before reperfusion reduced the myocardial infarct area at 24 hours after reperfusion (by triphenyltetrazolium chloride, 44.9±3.9% versus 34.6±5.7%, P<0.05); improved the left ventricular ejection fraction (by echocardiography), with less myocardial fibrosis (by Masson's staining), and prevented microvascular dysfunction (by immunofluorescence) at 28 days after reperfusion; and reduced myocardial pro‐NTs expression at 24 hours and 28 days after reperfusion (by Western blotting). A simulative IRI model using rat microvascular pericytes was established in vitro by hypoxia–reoxygenation (2/6 hours) combined with pro‐NTs treatment (3 nmol/L) at R. p75ECD (3 μg/mL) given at R improved pericyte survival (by methyl thiazolyl tetrazolium assay) and attenuated apoptosis (by terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick‐end labeling). In the reperfused hearts and hypoxia–reoxygenation +pro‐NTs‐injured pericytes, p75ECD inhibited the expression of p‐JNK (phospho of c‐Jun N‐terminal kinase)/caspase‐3 (by Western blotting). SP600125, an inhibitor of JNK, did not enhance the p75ECD‐induced infarct‐sparing effects and pericyte protection. Conclusions p75ECD may attenuate myocardial IRI via pro‐NTs reduction‐induced inhibition of p‐JNK/caspase‐3 pathway of microvascular pericytes in rats.

Keywords

• c‐Jun N‐terminal kinase
• extracellular domain
• microvascular dysfunction
• neurotrophin receptor
• pericyte
• reperfusion injury