MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

Abstract

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.

Contrast Media-Induced Renal Inflammation Is Mediated Through HMGB1 and Its Receptors in Human Tubular Cells

“…various biological activities, including mediated inflammatory response and immune response (Chen and Zhou, 2015). MCP-1 is one of the most important cell factors in the chemotaxis of monocytes/macrophages to renal tissue, which lead to a large number of monocytes/macrophages in the lesion (Donadelli et al, 2000;Niu et al, 2015). The activation of NF-kB and downstream release of IL-6 and MCP-1 were found in our study, emphasizing the vital role of inflammation in CIN.…”

MCPIP mediates preconditioning protection against ischemia

“…Cardiomyocyte-targeted expression of MCPIP protected against endotoxin-induced myocardial inflammation and dysfunction 12 . The level of MCPIP was also significantly increased in the murine heart after ligation of left coronary artery 13 . Mice with cardiomyocytetargeted expression of MCPIP showed improved survival, decreased cardiac hypertrophy, lower fibrosis and scar formation as well as better left ventricular function after myocardial infarction 13 .…”

“…The level of MCPIP was also significantly increased in the murine heart after ligation of left coronary artery 13 . Mice with cardiomyocytetargeted expression of MCPIP showed improved survival, decreased cardiac hypertrophy, lower fibrosis and scar formation as well as better left ventricular function after myocardial infarction 13 . MCPIP overexpressing murine heart also showed decreased monocytic cell infiltration and inflammatory cytokine expression as well as lower caspase 3/7 activities and apoptotic cell death compared to wild type mice 13 .These protective effects of MCPIP probably involve its ability to inhibit NF-κB activation as the MCPIP expressing murine hearts showed lower NF-κB signaling 12,13 .…”

“…Mice with cardiomyocytetargeted expression of MCPIP showed improved survival, decreased cardiac hypertrophy, lower fibrosis and scar formation as well as better left ventricular function after myocardial infarction 13 . MCPIP overexpressing murine heart also showed decreased monocytic cell infiltration and inflammatory cytokine expression as well as lower caspase 3/7 activities and apoptotic cell death compared to wild type mice 13 .These protective effects of MCPIP probably involve its ability to inhibit NF-κB activation as the MCPIP expressing murine hearts showed lower NF-κB signaling 12,13 . The anti-Dicer activity of MCPIP is also involved in its protection against ischemic damage as the MCPIP expressing murine hearts showed lower expression of inflammation-associated miR-126,-1461,-155 and -199a when compared to the post-infarct hearts of the wild type mice 13 .…”

Hesperetin protects against inflammatory response and cardiac fibrosis in postmyocardial infarction mice by inhibiting nuclear factor κB signaling pathway

“…Inflammatory cytokines and myocardial fibrosis form a complex regulatory network and the levels of inflammatory factors are closely linked to the degree of cardiac fibrosis (1,2). Therefore, the protective effect of hesperetin may be associated with the following mechanisms: First, hesperetin significantly inhibited NF-κB signaling pathway activation; NF-κB is a key regulator of the inflammatory response, whose activation promotes inflammation and induces the production of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, and it has been demonstrated that pro-inflammatory cytokines exert their effects on cardiomyocytes through activating NF-κB after MI (23,24). Furthermore, hesperetin inhibited cardiac fibrosis induced by inflammatory factors; inflammatory cytokines not only stimulate the synthesis of extracellular matrix in cardiac fibroblasts, but also reduce the number of cardiomyocytes by causing cardiac necrosis and apoptosis after MI, resulting in cardiac fibrosis (25).…”