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

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 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. Electronic supplementary material The online version of this article (10.1186/s12916-019-1268-y) contains supplementary material, which is available to authorized users.

Cathelicidin‐related antimicrobial peptide protects against ischaemia reperfusion‐induced acute kidney injury in mice

“…In addition, ours and other studies have shown that CRAMP directly attenuates stimuli‐triggered inflammatory responses in various cell types by directly interacting with bacterial endotoxin, activating pattern recognition receptors, or affecting intracellular inflammatory signalling (Hilchie et al, ; Mookherjee et al, ; Sun et al, ). Further, we also demonstrated that CRAMP could prevent cellular apoptosis by modulating apoptotic pathways and associated proteins (Bei et al, ; Sun et al, ).…”

“…Our recent work has demonstrated that peripheral non‐immune cells are a source of CRAMP with cytoprotective and immunomodulatory actions (Bei et al, ; Sun, Furio, et al, ; Sun et al, ). In this study, we extended our investigations to analyse the effects of CRAMP on renal I/R injury and the underlying mechanisms.…”

“…As a traditional AMP with increasing recognized host defence functions, roles of cathelicidin in inflammatory, immunological, and cardiovascular disorders have been earlier documented (Bei et al, ; Diana et al, ; Gilliet & Lande, ; Soehnlein et al, ; Sun, Furio, et al, ). In renal tissues, CRAMP is mainly expressed in tubular epithelium and by infiltrating leukocytes, including neutrophils and monocytes (Ali, Townes, Hall, & Pickard, ; Zasloff, ).…”

Catechin relieves hypoxia/reoxygenation‐induced myocardial cell apoptosis via down‐regulating lncRNA MIAT

“…5 Myocardial cell apoptosis mainly occurs in the surviving portion of the heart which contributes to the loss of myocardial cells and inhibits left ventricular remodelling after MI/R injury, and the increase in myocardial cell apoptosis is positively correlated with the occurrence of cardiac failure after MI/R injury. 7,8 Therefore, inhibiting myocardial cell apoptosis is important for the prevention and treatment of MI/R injury. 7,8 Therefore, inhibiting myocardial cell apoptosis is important for the prevention and treatment of MI/R injury.…”

“…6 So, apoptosis of myocardial cells is a key promoting factor contributing to cardiac failure after MI/R injury. 7,8 Therefore, inhibiting myocardial cell apoptosis is important for the prevention and treatment of MI/R injury.…”