Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction
Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction
复制标题
抑制肽基精氨酸脱亚胺酶 4 可预防心肌梗塞引起的心功能障碍
DOI：
10.1016/j.intimp.2019.106055
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Xue, Song
中科院分区：
文献类型：
--
作者：
Du, Mingjun;Yang, Wengang;Xue, Song
肽基精氨酸脱亚氨酶-4(PAD4)是PAD酶家族成员之一，催化靶蛋白中精氨酸残基翻译后转化为瓜氨酸。尽管PAD4被认为在感染性疾病、自身免疫性疾病和缺血性疾病等多种病理条件下发挥重要作用，但PAD4在心肌梗死(MI)所致心脏损伤中的作用仍有待研究。在这里，我们假设PAD4在MI后通过加剧炎症反应和促进中性粒细胞细胞外陷阱(NET)的形成而促进心脏缺血损伤。永久性左冠状动脉结扎，一种模拟MI的条件，在雄性C57BL/6小鼠上进行。[(3S，4R)-3-氨基-4-羟基-1-哌啶基][2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-benzimidazol-5-yl]-methanone(GSK484)是一种PAD4的抑制剂，通过腹腔注射抑制PAD4的活性。分析心肌PAD4表达、组织损伤评分、中性粒细胞浸润、Cit-H3表达、Net形成、炎性细胞因子分泌、细胞凋亡和心功能。GSK484介导的PAD4抑制可适度保护心肌梗死后的心室组织结构和心肌完整性，从而缩小心肌梗死范围，降低血清心肌酶水平。PAD4抑制也有效地保护心肌细胞免受MI诱导的Net形成和炎性细胞因子的分泌，从而减轻心肌缺血诱导的心肌细胞凋亡。综上所述，这些发现证明了特异性PAD4抑制在减少MI诱导的中性粒细胞浸润、Net形成、炎症反应和心肌细胞凋亡方面的有效性，从而促进整体心功能的改善。这些结果为开发治疗心肌梗死患者心血管功能障碍的新策略提供了新的见解。
Peptidyl arginine deiminase-4 (PAD4), a PAD enzyme family member, catalyzes the posttranslational conversion of arginine residues to citrulline in target proteins. Although PAD4 is believed to play a crucial role in various pathological conditions such as infectious diseases, autoimmune diseases, and ischemic conditions, the effect of PAD4 in myocardial infarction (MI)-induced cardiac injury remains to be examined. Here, we hypothesize that PAD4 contributes to cardiac ischemic injury by exacerbating the inflammatory response and promoting neutrophil extracellular trap (NET) formation after MI.Permanent left coronary artery ligation, a condition that mimics MI, was performed on male C57BL/6 mice. [(3S,4R)-3-amino-4-hydroxy-1-piperidinyl] [2- [1-(cyclopropylmethyl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-benzimidazol-5-yl]-methanone (GSK484), an inhibitor of PAD4, was delivered via intraperitoneal injection to inhibit PAD4 activity. Cardiac PAD4 expression, tissue injury scoring, neutrophil infiltration, cit-H3 expression, NET formation, inflammatory cytokine secretion, apoptosis, and cardiac function were analyzed.In the current study, we discovered the protective effect of PAD4 inhibition using the PAD4-specific inhibitor GSK484 in cardiomyocytes challenged by MI. GSK484-mediated PAD4 inhibition can moderately preserve ventricle histological structure and myocardium integrity after MI, thereby reducing the infarct size and decreasing myocardial enzyme levels in serum. PAD4 inhibition also effectively protects cardiomyocytes from MI-induced NET formation and inflammatory cytokine secretion, in turn alleviating cardiac ischemia-induced apoptosis of cardiomyocytes.Collectively, these findings demonstrate the efficacy of specific PAD4 inhibition in reducing MI-induced neutrophil infiltration, NET formation, inflammatory reaction, and cardiomyocyte apoptosis, thereby increasing overall cardiac function improvement. These results provide novel insights for the development of new strategies to treat cardiovascular dysfunction in MI patients.