Published online before print March 30, 2006, doi: 10.1161/01.RES.0000220106.64661.71
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Submitted on June 22, 2005
Revised on March 16, 2006
Accepted on March 22, 2006
Monocyte Chemoattractant Protein-1 Induces a Novel Transcription Factor That Causes Cardiac Myocyte Apoptosis and Ventricular Dysfunction
Limei Zhou ;
From the Burnett College of Biomedical Sciences (L.Z., A.A., J.N., S.G., M.C., F.M.A., C.Y., P.E.K.), University of Central Florida, Orlando; Dorothy M. Davis Heart and Lung Research Institute and the Division of Cardiovascular Medicine of the Ohio State University (P.F.B.), Columbus.
* To whom correspondence should be addressed. E-mail: pk{at}mail.ucf.edu.
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 HEK293 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.
Key words: MCP-1 • MCP-induced protein (MCPIP), • monocyte/macrophages • MCP-1-induced transcription factor • MCPIP-induced cell death
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