Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-β1 transgene in the heart

Abstract

Increased transforming growth factor (TGF)-βv1 activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-β1 in this process, transgenic mice with elevated levels of active myocardial TGF-β1 were generated. The cardiac-restricted α-myosin heavy chain promoter was used to target expression of a mutant TGF-β1 cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-β1 latent complex to the extracellular matrix, thereby rendering a large proportion (>60%) of the transgene-encoded TGF-β1 constitutively active. Although similar levels of active TGF-β1 were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-β1 levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-β1 activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.