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
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Journal of the American Heart Association - 9(2020), 13 vom: 07. Juli, Seite e016047 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fang, Jun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.03.2021 Date Revised 09.03.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1161/JAHA.119.016047 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM311460984 |
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| 024 | 7 | |a 10.1161/JAHA.119.016047 |2 doi | |
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| 041 | |a eng | ||
| 100 | 1 | |a Fang, Jun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2020 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 09.03.2021 | ||
| 500 | |a Date Revised 09.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a c‐Jun N‐terminal kinase | |
| 650 | 4 | |a extracellular domain | |
| 650 | 4 | |a microvascular dysfunction | |
| 650 | 4 | |a neurotrophin receptor | |
| 650 | 4 | |a pericyte | |
| 650 | 4 | |a reperfusion injury | |
| 650 | 7 | |a Peptide Fragments |2 NLM | |
| 650 | 7 | |a Receptor, Nerve Growth Factor |2 NLM | |
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| 650 | 7 | |a Casp3 protein, rat |2 NLM | |
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| 650 | 7 | |a Caspase 3 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 700 | 1 | |a Wei, ZhiXiong |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, DeDong |e verfasserin |4 aut | |
| 700 | 1 | |a Ying, Teng |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, HuaShan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, DanQing |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, YunLing |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, XiaoLiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, LingZhen |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, TingXiang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, ZhiWei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, XinFu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, LiangLong |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:9 |g year:2020 |g number:13 |g day:07 |g month:07 |g pages:e016047 |
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