Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury

• Published in: BMC medicine Vol. 17; no. 1; p. 42
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.02.2019; BioMed Central; BMC
• Subjects: Activation; AKT protein; Animals; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Antiinfectives and antibacterials; Antimicrobial agents; Antimicrobial peptides; Apoptosis; c-Jun protein; Cardiomyocyte; Cardiomyocytes; Cardiovascular diseases; Care and treatment; Cathelicidin; Cathelicidins; Cathelicidins - pharmacology; Cathelicidins - therapeutic use; CRAMP; Deprivation; Diabetes; Exports; FOXO3 protein; Genes; Glucose; Health aspects; Heart; Heart attack; Heart attacks; Heart cells; Heart diseases; Humans; Hypoxia; Immunity; Immunomodulation; Inflammation; Inflammatory response; Injury prevention; Investigations; Ischemia; Ischemia/reperfusion injury; Kinases; Laboratory animals; LL-37; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Microvasculature; Myocardial infarction; Myocardial ischemia; Myocardial Reperfusion Injury - drug therapy; Neonates; Neutrophils; Newborn infants; Novels; Nuclear transport; Oxidative stress; Patients; Peptides; Phosphorylation; Proteins; Reperfusion; Rodents; Signal transduction; Transcription factors; China; Cathelicidin; CRAMP; Ischemia/reperfusion injury; LL-37; Cardiomyocyte; Apoptosis
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-019-1268-y

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 cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown. 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. 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. 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.