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
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Date
2020
Authors
Fang, J.
Wei, Z.
Zheng, D.
Ying, T.
Hong, H.
Hu, D.
Lin, Y.
Jiang, X.
Wu, L.
Lan, T.
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Journal article
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Journal of the American Heart Association, 2020; 9(13):1-24
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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.
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Data source: Supplementary Materials, https://doi.org/10.1161/JAHA.119.016047
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Copyright 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. (https://creativecommons.org/licenses/by-nc-nd/4.0/)