Dataset Information

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.

SUBMITTER: Bei Y

PROVIDER: S-EPMC6381635 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Bei Yihua Y Pan Li-Long LL Zhou Qiulian Q Zhao Cuimei C Xie Yuan Y Wu Chengfei C Meng Xiangmin X Gu Huanyu H Xu Jiahong J Zhou Lei L Sluijter Joost P G JPG Das Saumya S Agerberth Birgitta B Sun Jia J Xiao Junjie J

BMC medicine 20190220 1

<h4>Background</h4>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 unk ...[more]

PMID: 30782145

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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