论文标题：Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury

期刊：BMC Medicine

作者： Yihua Bei†, Li-Long Pan†, Qiulian Zhou†, Cuimei Zhao, Yuan Xie, Chengfei Wu, Xiangmin Meng, Huanyu Gu, Jiahong Xu, Lei Zhou, Joost P. G. Sluijter, Saumya Das, Birgitta Agerberth, Jia Sun and Junjie Xiao

发表时间：2019/02/20

数字识别码：10.1186/s12916-019-1268-y

原文链接：https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1268-y?utm_source=other&utm_

medium=other&utm_content=null&utm_campaign=BSCN_2_WX_Cathelicidin_Arti_Scinet

微信链接：https://mp.weixin.qq.com/s/7IKZfgbMZcpOXkRLvefDMQ

急性心肌梗死是严重危害人类健康的重大疾病，随着经皮冠状动脉介入等再灌注治疗的应用，急性心肌梗死患者的早期死亡率显著降低。但是，再灌注治疗也会导致再灌注损伤，最终引起严重的心室重构不良以及心力衰竭，目前尚缺乏干预的方法。

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抗菌肽Cathelicidin是一类宿主防御肽，参与调控免疫炎症反应。抗菌肽Cathelicidin的非抗菌活性正日益受到重视，包括对于心血管疾病炎症和微血管的功能调控作用。但是，抗菌肽Cathelicidin在心脏缺血再灌注损伤所致心肌细胞凋亡中的作用尚不清楚。近期，上海大学生命科学学院心血管研究所肖俊杰教授团队和江南大学孙嘉教授团队合作发现抗菌肽可以保护心脏缺血再灌注损伤，并明确其起效的分子机制。研究成果发表在国际知名医学期刊BMC Medicine上。

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同济大学、南京医科大学、荷兰乌特勒支大学、瑞典卡罗林斯卡医学院和哈佛大学的研究者也参与了该项目的研究。该研究工作得到了国家自然科学基金、上海市教委科研创新重大项目、上海市科委“科技创新行动计划”政府间国际合作项目等项目的资助。

此次研究发现，抗菌肽Cathelicidin在心脏缺血再灌注损伤模型小鼠的心脏和血清中的表达均显著降低。相较心脏成纤维细胞，抗菌肽Cathelicidin高表达于心肌细胞，且在氧葡萄糖剥夺恢复（OGDR）诱导心肌细胞凋亡的模型中显著降低。增加抗菌肽Cathelicidin可以减轻氧葡萄糖剥夺恢复（OGDR）诱导的心肌细胞凋亡，也可以减轻小鼠心脏缺血再灌注损伤。

相关的机制研究发现，抗菌肽Cathelicidin可以磷酸化AKT和ERK1/2，促进FoxO3a磷酸化及出核，抑制AKT和ERK1/2信号通路可以减轻抗菌肽Cathelicidin对于心肌细胞凋亡的保护效应，说明抗菌肽Cathelicidin是通过激活AKT、ERK1/2信号通路、促进FoxO3a磷酸化及出核，发挥抵抗心肌细胞凋亡的效应。

此外，研究人员还注意到，在入院急性心肌梗死患者血清，抗菌肽Cathelicidin含量显著降低，且血清抗菌肽Cathelicidin/中性粒细胞比值与急性心肌梗死患者一年内再入院或者死亡成负相关。

总的来说，这项合作研究发现了一个全新的防治心脏缺血再灌注损伤的方法：外源性增加抗菌肽Cathelicidin，并揭示了一个新的可以用于急性心肌梗死患者预后评估的生物标志物，具有潜在的未来临床转化的价值。

摘要：

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.

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期刊介绍:

BMC Medicine （https://bmcmedicine.biomedcentral.com/,9.088 - 2-year Impact Factor,9.41 - 5-year Impact Factor）is the flagship medical journal of the BMC series. An open access, open peer-reviewed general medical journal, BMC Medicine publishes outstanding and influential research in all areas of clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. We also publish stimulating debates and reviews as well as unique forum articles and concise tutorials.

（来源：科学网）