Fibroblast-specific TGF-b Signaling Protects The Infarcted Myocardium From Adipose Tissue Infiltration

Background and Objectives: Repair of the infarcted heart requires timely phenotypic transitions of fibroblasts, the central effector cells involved in scar formation and matrix remodeling. TGF-b superfamily members are critical regulators of fibroblast phenotype, acting through TGF-b receptors (TbR) and downstream activation of Smad-dependent and Smad-independent cascades. We have previously demonstrated that fibroblast-specific Smad3 plays a central role in repair of the infarcted heart; however, the role of TGF-b/TbR signaling in regulation of infarct fibroblast transitions has not been investigated. In the current study we examine the role of fibroblast-specific TGF-b signaling in repair of the infarcted heart, using mice with inducible fibroblast-specific disruption of TbRII (FTbRIIKO mice), the only type 2 receptor mediating the effects of all 3 TGB-b isoforms. Findings: FTbRIIKO animals exhibited increased mortality after myocardial infarction (MI), caused by cardiac rupture. In comparison with TbRII fl/fl mice, TbRII KO mice had significant thinning of the anterior wall 28 days after MI, without significant differences in ventricular function. Fibroblast-specific TGF-b signaling loss did not affect myofibroblast infiltration 7 days after MI. 28 days after MI, brightfield and polarized microscopy showed that, although scar size was comparable between the groups, collagen content and the width of collagen fibers were reduced within infarcted zones of FTbRIIKO vs. FTbRII fl/fl animals. Moreover, FTbRIIKO mice exhibited a striking deposition of adipocytes, occupying up to 40% of the infarct zones (fatty infiltration: FTbRIIKO, 28.7±6.2% vs floxed 0±0%, p<0.001, n=6-8). Infarct fibroblasts harvested from FTbRIIKO mice 7 days after MI had increased expression of adipocyte genes, such as perilipin, leptin receptor, and PPARgamma. Conclusions: Fibroblast-specific TGF-β signaling protects the infarcted heart from cardiac rupture and prevents fatty infiltration of the infarct. These effects may reflect critical actions of TGF-bs on fibroblast phenotypic transitions and inhibition of fibroblast to adipocyte conversion.