Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury
Bei, Yihua; Pan, Li Long; Zhou, Qiulian; Zhao, Cuimei; Xie, Yuan; Wu, Chengfei; Meng, Xiangmin; Gu, Huanyu; Xu, Jiahong; Zhou, Lei; Sluijter, Joost P.G.; Das, Saumya; Agerberth, Birgitta; Sun, Jia; Xiao, Junjie
(2019) BMC Medicine, volume 17, issue 1
(Article)
Abstract
Background: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of
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cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown. Methods: CRAMP (cathelicidin-related antimicrobial peptide) levels were measured in the heart and serum from I/R mice and in neonatal mouse cardiomyocytes treated with oxygen glucose deprivation/reperfusion (OGDR). Human serum cathelicidin antimicrobial peptide (LL-37) levels were measured in myocardial infarction (MI) patients. The role of CRAMP in myocardial apoptosis upon I/R injury was investigated in mice injected with the CRAMP peptide and in CRAMP knockout (KO) mice, as well as in OGDR-treated cardiomyocytes. Results: We observed reduced CRAMP level in both heart and serum samples from I/R mice and in OGDR-treated cardiomyocytes, as well as reduced LL-37 level in MI patients. Knockdown of CRAMP enhanced cardiomyocyte apoptosis, and CRAMP KO mice displayed increased infarct size and myocardial apoptosis. In contrast, the CRAMP peptide reduced cardiomyocyte apoptosis and I/R injury. The CRAMP peptide inhibited cardiomyocyte apoptosis by activation of Akt and ERK1/2 and phosphorylation and nuclear export of FoxO3a. c-Jun was identified as a negative regulator of the CRAMP gene. Moreover, lower level of serum LL-37/neutrophil ratio was associated with readmission and/or death in MI patients during 1-year follow-up. Conclusions: CRAMP protects against cardiomyocyte apoptosis and cardiac I/R injury via activation of Akt and ERK and phosphorylation and nuclear export of FoxO3a. Increasing LL-37 might be a novel therapy for cardiac ischemic injury.
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Keywords: Apoptosis, Cardiomyocyte, Cathelicidin, CRAMP, Ischemia/reperfusion injury, LL-37, General Medicine
ISSN: 1741-7015
Publisher: BioMed Central
Note: Funding Information: This work was supported by the grants from National Natural Science Foundation of China (81722008 to J.J.X., 81600228 to C.Z., 91639101 and 81570362 to J.J.X., 81770401 to Y.B., 91642114 to J.S., 81573420 to L.P.), National Key Research and Development Program of China (2017YFC1700401 to Y.B.), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to J.J.X.), the grant from Science and Technology Commission of Shanghai Municipality (18410722200 and 17010500100 to J.J.X.), the development fund for Shanghai talents (T. 39-0112-17-201 to J.J.X.), the grant from Shanghai Municipal Health Commission (20154Y0026 to C.Z.), Jiangsu Province Recruitment Plan for High-level, Innovative and Entrepreneurial Talents to J.S., Fundamental Research Funds for the Central Universities (JUSRP51613A to J.S., JUSRP11866 to L.P.), Wuxi Science & Technology Development Funds for International Science & Technology R&D Cooperation (WX0303B010518180007PB to J.S.), National First-class Discipline Program of Food Science and Technology (JUFSTR20180103 to J.S.), and the National Institutes of Health (NCATS grant UH3 TR000901 to S.D.). Publisher Copyright: © 2019 The Author(s).
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