Copyright © 2006, European Society of Cardiology
Monocyte-specific Bcl-2 expression attenuates inflammation and heart failure in monocyte chemoattractant protein-1 (MCP-1)-induced cardiomyopathy
Biomolecular Science Center and Department of Molecular Biology and Microbiology, Burnett College of Biomedical Science, University of Central Florida, FL 32816, USA
* Corresponding author. Tel.: +1 407 823 1206; fax: +1 407 823 0956. Email address: jniu{at}mail.ucf.edu aazfer{at}mail.ucf.edu pk{at}mail.ucf.edu
Objective Infiltrating inflammatory cells within the myocardium have been shown to be apoptotic, but the significance of apoptotic inflammatory cells to the development of cardiomyopathy remains undefined. Transgenic mice with cardiac-specific expression of MCP-1 exhibit extensive apoptosis of infiltrating mononuclear cells and develop heart failure. Here, we tested the hypothesis that in vivo selective inhibition of apoptosis of infiltrating mononuclear cells would preserve cardiac structure and function and improve survival in this murine model.
Methods Mice with cardiac-specific expression of MCP-1 and monocyte-specific expression of Bcl-2 were generated by cross-breeding MCP-1 transgenic mice with hMRP8-Bcl-2 mice that over-express Bcl-2 in the monocytes. Structural and functional parameters and the inflammatory response of the heart were evaluated and compared between the wild-type and transgenic mice.
Results Expression of Bcl-2 in monocytes results in superior preservation of myocardial structure, cardiac function and a significant prolongation of survival of MCP-1 transgenic mice. The beneficial effects of monocyte-specific Bcl-2 expression are associated with inhibition of apoptosis of infiltrating mononuclear cells, normalization of circulating C-reactive protein levels, attenuation of cellular infiltrates, macrophage activation and production of proinflammatory cytokines, tumor necrosis factor (TNF-
), interleukin (IL)-1β and IL-6 in the hearts.
Conclusions These results demonstrate that apoptosis of infiltrating mononuclear cells plays a detrimental role in the development of heart failure in this murine model, suggesting that modulation of apoptosis of infiltrating mononuclear cells may be of clinical benefit in heart failure.
KEYWORDS Inflammation; Monocyte chemoattractant protein-1; Apoptosis; Cardiomyopathy; Transgenic animal model
1 The authors made equal contributions.
Time for primary review 27 days
This work was presented in part at the 2005 Scientific Sessions of the American Heart Association, Dallas, Texas, USA, in November 2005.
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