Monocyte Chemoattractant Protein-1 Induces A Novel Transcription Factor That Causes Cardiac Myocyte Apoptosis And Ventricular Dysfunction

Monocyte chemoattractant protein-1 (MCP-1; CCL2)-mediated inflammation plays a critical role in the development of ischemic heart disease (IHD). However, the gene expression changes caused by signal transduction, triggered by MCP-1 binding to its receptor CCR2, and their possible role in the development of IHD are not understood. We present evidence that MCP-1 binding to CCR2 induces a novel transcription factor (MCP-induced protein [MCPIP]) that causes cell death. Gene microarray analysis showed that when expressed in hiuman embryonic kidney 293 cells, MCPIP induced apoptotic gene families before causing cell death. Mutagenesis studies showed that the structural features required for transcription factor-like activity were also required for causing cell death. Activation of caspase-3 was detected after MCPIP transfection and Z-VAD-fmk partially inhibited cell death. Cardiomyocyte-targeted expression of MCP-1 in mice caused death by heart failure at 6 months of age. MCPIP expression increased in parallel with the development of ventricular dysfunction. In situ hybridization showed the presence of MCPIP transcripts in the cardiomyocytes and immunohistochemistry showed that MCPIP was associated with the cardiomyocyte nuclei of apoptotic cardiomyocytes. CCR2 expression in cardiomyocytes increased with the development of IHD. MCPIP production induced by MCP-1 binding to CCR2 in the cardiomyocytes is probably involved in the development of IHD in this murine model. MCPIP transcript levels were much higher in the explanted human hearts with IHD than with nonischemic heart disease. These results provide a molecular insight into how chronic inflammation and exposure to MCP-1 contributes to heart failure and suggest that MCPIP could be a potential target for therapeutic intervention. © 2006 American Heart Association, Inc

Mcp-1-Induced Protein Attenuates Endotoxin-Induced Myocardial Dysfunction By Suppressing Cardiac Nf-Κb Activation Via Inhibition Of Iκb Kinase Activation

Myocardial contractile dysfunction is a major consequence of septic shock, which is mainly mediated by nuclear factor-kappa B (NF-κB)-dependent production of inflammatory mediators in the heart. A novel zinc-finger protein, MCP-1-induced protein (MCPIP), is thought to have NF-κB inhibitory activity in certain cell cultures, but its pathophysiological consequence in vivo remains undefined. This study aims to clarify whether the anti-inflammatory potency of MCPIP contribute to amelioration of septic myocardial inflammation and dysfunction in vivo. Transgenic mice (TG) with cardiac-specific expression of MCPIP and their littermate wild-type (WT) controls were challenged with Escherichia coli LPS (10. mg/kg ip) and myocardial function was assessed 18. h later using echocardiography. LPS administration markedly deteriorated myocardial contractile function evidenced by reduction of the percentage of left ventricular fractional shortening, which was significantly attenuated by myocardial expression of MCPIP. MCPIP TG mice exhibited a markedly reduced myocardial inflammatory cytokines, less of iNOS expression and peroxynitrite formation, decreased caspase-3/7 activities and apoptotic cell death compared with LPS-treated WT mice. Activation of cardiac NF-κB observed in LPS-challenged WT mice was suppressed by the presence of MCPIP, as evidenced by decreased phosphorylation of IκB kinase (IKKα/β), reduced degradation of the cytosolic IκBα, and decreased nuclear translocation of NF-κB p65 subunit and its target DNA-binding activity. These results suggest that MCPIP has therapeutic values to protect heart from inflammatory pathologies, possibly through inhibition of IκB kinase complex, leading to blockade of NF-κB activation, and subsequently, attenuation of the proinflammatory state and nitrosative stress in the myocardium. © 2011 Elsevier Ltd