Title

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

Keywords

Endotoxin; Inflammation; MCPIP; Myocardial dysfunction; NF-κB; Shock

Abstract

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.

Publication Date

8-1-2011

Publication Title

Journal of Molecular and Cellular Cardiology

Volume

51

Issue

2

Number of Pages

177-186

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.yjmcc.2011.04.018

Socpus ID

79959521145 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/79959521145

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