Niu Jianli, Jin Zhuqing, Kim Hyunbae, Kolattukudy Pappachan E
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA,
Basic Res Cardiol. 2015 May;110(3):26. doi: 10.1007/s00395-015-0483-8. Epub 2015 Apr 4.
MCP-1-induced protein (MCPIP, also known as ZC3H12A) has recently been uncovered to act as a negative regulator of inflammation. Expression of MCPIP was elevated in the ventricular myocardium of patients with ischemic heart failure. However, the role of MCPIP in the development of post-infarct cardiac inflammation and remodeling is unknown. The objective of the present study was to investigate whether MCPIP exerts an inhibitory effect on the cardiac inflammatory response and adverse remodeling after myocardial infarction (MI). Mice with cardiomyocyte-specific expression of MCPIP and their wild-type littermates (FVB/N) were subjected to permanent ligation of left coronary artery. The levels of MCPIP were significantly increased in the ischemic myocardium and sustained for 4 weeks after MI. Acute infarct size was comparable between groups. However, constitutive overexpression of MCPIP in the murine heart resulted in improved survival rate, decreased cardiac hypertrophy, less of fibrosis and scar formation, and better cardiac performance at 28 days after MI, along with a markedly reduced monocytic cell infiltration, less cytokine expression, decreased caspase-3/7 activities and apoptotic cell death compared to the wild-type hearts. Cardiomyocyte-specific expression of MCPIP also attenuated activation of cardiac NF-κB signaling and expression of inflammation-associated microRNAs (miR-126, -146a, -155, and -199a) when compared with the post-infarct wild-type hearts. In vitro, MCPIP expression suppressed hypoxia-induced NF-κB-luciferase activity in cardiomyocytes. In conclusion, MCPIP expression in the ischemic myocardium protects against adverse cardiac remodeling and dysfunction following MI by modulation of local myocardial inflammation, possibly through mitigating NF-κB signaling and suppressing inflammation-associated microRNA expression.
单核细胞趋化蛋白-1诱导蛋白（MCPIP，也称为ZC3H12A）最近被发现可作为炎症的负调节因子。在缺血性心力衰竭患者的心室心肌中，MCPIP的表达升高。然而，MCPIP在心肌梗死后心脏炎症和重塑发展中的作用尚不清楚。本研究的目的是调查MCPIP是否对心肌梗死后的心脏炎症反应和不良重塑具有抑制作用。对具有心肌细胞特异性表达MCPIP的小鼠及其野生型同窝小鼠（FVB/N）进行左冠状动脉永久性结扎。缺血心肌中MCPIP的水平显著升高，并在心肌梗死后持续4周。各组之间急性梗死面积相当。然而，与野生型心脏相比，小鼠心脏中MCPIP的组成型过表达导致心肌梗死后28天生存率提高、心脏肥大减轻、纤维化和瘢痕形成减少、心脏功能改善，同时单核细胞浸润明显减少、细胞因子表达减少、半胱天冬酶-3/7活性降低和凋亡细胞死亡减少。与心肌梗死后的野生型心脏相比，MCPIP的心肌细胞特异性表达还减弱了心脏NF-κB信号通路的激活以及炎症相关微小RNA（miR-126、-146a、-155和-199a）的表达。在体外，MCPIP的表达抑制了心肌细胞中缺氧诱导的NF-κB荧光素酶活性。总之，缺血心肌中MCPIP的表达通过调节局部心肌炎症，可能通过减轻NF-κB信号通路和抑制炎症相关微小RNA的表达，预防心肌梗死后的不良心脏重塑和功能障碍。
