Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury
Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury
复制标题
导管素相关抗菌肽可预防心肌缺血/再灌注损伤
DOI：
10.1186/s12916-019-1268-y
复制
发表时间：
2019-02-20
期刊：
影响因子：
9.3
通讯作者：
Xiao, Junjie
中科院分区：
文献类型：
--
作者：
Bei, Yihua;Pan, Li-Long;Xiao, Junjie
研究背景Cathelicidins是一类重要的天然抗菌肽，在调节机体防御和免疫功能中发挥重要作用。除了抗微生物和免疫调节活性外，最近的研究报道了cathelicidins通过调节炎症反应和微血管功能障碍参与心血管疾病。然而，cathelicidins在心肌缺血/再灌注（I/R）损伤后的心肌细胞凋亡中的作用仍然在很大程度上unknown.MethodsCRAMP（cathelicidin-related antimicrobial peptide，cathelicidin相关的抗菌肽）水平测定在心脏和血清中从I/R小鼠和新生小鼠心肌细胞处理与氧葡萄糖剥夺/再灌注（OGDR）。测定了心肌梗死（MI）患者血清凯萨林菌素抗菌肽（LL-37）水平。CRAMP在心肌细胞凋亡中的作用I/R损伤后，在小鼠注射CRAMP肽和CRAMP基因敲除（KO）小鼠，以及在OGDR-治疗的cardiomyocytes.ResultsWe观察到降低CRAMP水平在心脏和血清样品从I/R小鼠和OGDR-治疗的心肌细胞，以及降低LL-37水平在MI患者。CRAMP基因敲除可增强心肌细胞凋亡，CRAMP基因敲除小鼠梗死面积增加，心肌细胞凋亡增加。相反，CRAMP肽减少心肌细胞凋亡和I/R损伤。CRAMP肽通过激活Akt和ERK 1/2以及FoxO 3a的磷酸化和核输出来抑制心肌细胞凋亡。c-Jun被鉴定为CRAMP基因的负调节因子。此外，较低水平的血清LL-37/中性粒细胞比率与再入院和/或死亡在MI患者在1年follow-up.ConclusionsCRAMP通过激活Akt和ERK和磷酸化和FoxO 3a的核输出，保护心肌细胞凋亡和心脏I/R损伤。增加LL-37可能是治疗心肌缺血性损伤的一种新方法。
BackgroundCathelicidins 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.MethodsCRAMP (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.ResultsWe 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.ConclusionsCRAMP 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.