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(Circulation Research. 2000;86:571.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Atrial but Not Ventricular Fibrosis in Mice Expressing a Mutant Transforming Growth Factor-ß₁ Transgene in the Heart

Hidehiro Nakajima, Hisako O. Nakajima, Olga Salcher, Andrea S. Dittiè, Klaus Dembowsky, Shaoliang Jing, Loren J. Field

From the Herman B. Wells Center for Pediatric Research and Krannert Institute of Cardiology (H.N., H.O.N., S.J., L.J.F.), Indiana University School of Medicine, Indianapolis, Ind, and the Department of Molecular Screening and Technology (O.S.) and the Institute of Cardiovascular Research (A.S.D., K.D.), Bayer AG, Pharma Research Center, Wuppertal, Germany.

Correspondence to Loren J. Field, Herman B Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr, Room 2666, Indianapolis, IN 46202-5225. E-mail ljfield{at}iupui.edu

Abstract—Increased transforming growth factor (TGF)–ß₁ activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-ß₁ in this process, transgenic mice with elevated levels of active myocardial TGF-ß₁ were generated. The cardiac-restricted –myosin heavy chain promoter was used to target expression of a mutant TGF-ß₁ cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-ß₁ latent complex to the extracellular matrix, thereby rendering a large proportion (>60%) of the transgene-encoded TGF-ß₁ constitutively active. Although similar levels of active TGF-ß₁ were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-ß₁ levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-ß₁ activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.

Key Words: heart failure • cardiac fibroblast proliferation • extracellular matrix • collagen • cytokine

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