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Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload

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Abstract

Myocardial fibrosis is an integral component of most cardiac pathologic conditions and contributes to the development of both systolic and diastolic dysfunction. Because of the availability of genetically manipulated animals, mouse models are essential for understanding the mechanisms involved in the pathogenesis of cardiac fibrosis. Accordingly, we characterized the inflammatory and fibrotic response in a mouse model of cardiac pressure overload due to transverse aortic constriction (TAC). Following TAC, mouse hearts exhibited induction of chemokines and proinflammatory cytokines, associated with macrophage, but not neutrophil, infiltration. Induction of inflammatory cytokines was followed by a late upregulation of transforming growth factor (TGF)-β isoforms, activation of the Smad2/3 and Smad1/5 pathways, induction of matricellular proteins, and deposition of collagen. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted, accompanied by ventricular dilation and systolic dysfunction. Late induction of inhibitory mediators, such as TGF-β, may play an essential role in the transition from inflammation to fibrosis by suppressing inflammatory gene synthesis while inducing matrix deposition. Our findings identify molecular mediators and pathways with a potential role in cardiac fibrosis laying the foundations for studies exploring the pathogenesis of fibrotic cardiac remodeling using genetically targeted mice.

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Acknowledgments

Supported by NIH R01 HL-76246 and HL-85440.

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Correspondence to Nikolaos G. Frangogiannis.

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Xia, Y., Lee, K., Li, N. et al. Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload. Histochem Cell Biol 131, 471–481 (2009). https://doi.org/10.1007/s00418-008-0541-5

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