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SMAD3 SIGNALING CRITICALLY REGULATES INFARCT HEALING
Author(s) -
Bujak Marcin J,
Ren Guofeng,
Chatila Khaled F,
Dobaczewski Marcin,
Reddy Anilkumar,
Taffet George,
Wang XiaoFan,
Frangogiannis Nikolaos G
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a11-a
Subject(s) - extracellular matrix , ventricle , fibrosis , ventricular remodeling , infarction , medicine , fibroblast , wound healing , downregulation and upregulation , endocrinology , microbiology and biotechnology , chemistry , myocardial infarction , biology , immunology , cell culture , biochemistry , genetics , gene
Optimal infarct healing requires timely activation and resolution of inflammatory pathways and transition to fibrous tissue deposition. TGF‐β regulates leukocyte recruitment, suppresses pro‐inflammatory cytokine synthesis and promotes fibrosis by modulating fibroblast gene expression. We examined the role of Smad3 signaling in regulating healing and post‐infarction cardiac remodeling using a mouse model of reperfused infarction and isolated fibroblasts from WT and Smad3 −/− hearts. Smad3 −/− mice exhibited decreased dilation of the infarcted ventricle, attenuated systolic and diastolic dysfunction and reduced left ventricular end‐diastolic pressure in comparison with WT animals. Smad3 −/− mice had similar macrophage infiltration and decreased neutrophil recruitment in the infarct and exhibited timely resolution of the inflammatory response. However, Smad3 null animals showed decreased collagen expression in the infarcted heart and less extensive deposition of tenascin‐C, a marker of interstitial remodeling, in the infarct border zone. TGF‐β markedly upregulated TIMP‐1 and TIMP‐2 mRNA expression in WT, but not Smad3 null cardiac fibroblasts, suggesting that the effects of TGF‐β on their matrix‐degrading properties are Smad3‐dependent. Smad3 deficiency decreases post‐infarction remodeling through effects on extracellular matrix deposition and metabolism.