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.
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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神经营养素受体 p75 的重组胞外结构域 (p75ECD) 通过抑制大鼠微血管周细胞中的 p-JNK/Caspase-3 信号通路减轻心肌缺血再灌注损伤
DOI：
10.1161/jaha.119.016047
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发表时间：
2020-07-07
影响因子：
5.4
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Fang J;Wei Z;Zheng D;Ying T;Hong H;Hu D;Lin Y;Jiang X;Wu L;Lan T;Yang Z;Zhou X;Chen L
神经营养因子前体（Pro-NTs）及其受体p75是预防心肌缺血再灌注损伤（IRI）诱导的微血管功能障碍的潜在靶点。p75 ECD（神经营养因子受体p75的胞外域）可能通过清除pro-NT产生生理性神经细胞保护作用。因此，我们假设p75 ECD可能通过微血管机制对IRI具有心脏保护作用。通过在随后放松之前闭塞左冠状动脉主干45分钟，在Sprague-道利大鼠中诱导心肌IRI。与缺血再灌注组相比，再灌注前5 min静脉注射p75 ECD（3 mg/kg）可减少再灌注后24 h的心肌梗死面积氯化三苯基四氮唑组为44.9±3.9%，对照组为34.6± 5.7%，P<0.05;改善左心室射血分数（通过超声心动图），心肌纤维化较少（通过Masson染色），并在再灌注后28天防止微血管功能障碍（通过免疫荧光）;并在再灌注后24小时和28天减少心肌pro-NTs表达（通过Western印迹）。采用缺氧-复氧（2/6小时）结合pro-NTs处理（3 nmol/L）在R.在R时给予p75 ECD（3 μg/mL）可改善周细胞存活（通过甲基噻唑基四唑测定）并减弱凋亡（通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记）。在再灌注心脏和缺氧-复氧+pro-NTs-损伤的周细胞中，p75 ECD抑制p-JNK（c-Jun N-末端激酶磷酸化）/caspase-3的表达（通过Western印迹法）。JNK抑制剂SP 600125不能增强p75 ECD诱导的梗死保留效应和周细胞保护作用。p75 ECD可能通过减少pro-NTs诱导的大鼠微血管周细胞p-JNK/caspase-3途径的抑制来减轻心肌IRI。
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. 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. p75ECD may attenuate myocardial IRI via pro‐NTs reduction‐induced inhibition of p‐JNK/caspase‐3 pathway of microvascular pericytes in rats.