TY - JOUR
T1 - Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload
AU - Xia, Ying
AU - Lee, Keunsang
AU - Li, Na
AU - Corbett, Daniel
AU - Mendoza, Leonardo
AU - Frangogiannis, Nikolaos G.
N1 - Funding Information:
Acknowledgments Supported by NIH R01 HL-76246 and HL-85440.
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
KW - Cardiac fibrosis
KW - Chemokine
KW - Cytokine
KW - Inflammation
KW - TGF-β
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U2 - 10.1007/s00418-008-0541-5
DO - 10.1007/s00418-008-0541-5
M3 - Article
C2 - 19030868
AN - SCOPUS:64649102284
SN - 0948-6143
VL - 131
SP - 471
EP - 481
JO - Histochemistry and Cell Biology
JF - Histochemistry and Cell Biology
IS - 4
ER -