Abstract：
The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1β and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.
摘要：
我国心肌梗死的发病率和死亡率呈逐年上升趋势。巨噬细胞向经典活化的巨噬细胞（M1）表型的极化在心肌梗塞后的炎性应激的进展中至关重要。聚（ADP-核糖）聚合酶1（PARP1）是PARP家族中普遍存在且特征最好的成员，据报道，这支持巨噬细胞向促炎表型的极化。然而，PARP1在心肌缺血损伤中的作用仍有待阐明。这里,我们证明,心肌梗死小鼠模型诱导了以心功能不全为特征的心脏损伤,并增加了心肌巨噬细胞中PARP1的表达.PJ34抑制剂对PARP1的抑制作用可有效缓解M1巨噬细胞极化,减少梗死面积，减少炎症并挽救小鼠MI后的心功能。机械上,抑制PARP1增加NLRC5基因表达，从而抑制NF-κB通路,从而减少炎性细胞因子如IL-1β和TNF-α的产生。NLRC5的抑制通过有效消除上述这种机制的影响来促进感染。有趣的是,抑制NLRC5可促进心脏巨噬细胞向M1表型极化,但对M2巨噬细胞无重大影响.我们的结果表明，抑制PARP1增加NLRC5基因表达，从而抑制M1极化，改善心脏功能，减少梗死面积和减轻炎症损伤。上述发现为心肌梗死后驱动巨噬细胞极化的促炎机制提供了新的见解，从而为受心肌梗死影响的个体的未来治疗干预引入了新的潜在目标。
