Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart.
Increased transforming growth factor (TGF)-beta(1) activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-beta(1) in this process, transgenic mice with elevated levels of active myocardial TGF-beta(1) were generated. The cardiac-restricted alpha-myosin heavy chain promoter was used to target expression of a mutant TGF-beta(1) cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-beta(1) latent complex to the extracellular matrix, thereby rendering a large proportion (>60%) of the transgene-encoded TGF-beta(1) constitutively active. Although similar levels of active TGF-beta(1) were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-beta(1) levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-beta(1) activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.
Nakajima
H
H
Herman B. Wells Center for Pediatric Research and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Ind, USA.
Nakajima
H O
HO
Salcher
O
O
Dittiè
A S
AS
Dembowsky
K
K
Jing
S
S
Field
L J
LJ
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006325:Heart Atria / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D006333:Heart Failure / Q000235:genetics / Q000473:pathology; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D019076:Transgenes / Q000502:physiology; D014945:Wound Healing / Q000502:physiology
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D004247:DNA