TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.
Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-beta1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-beta1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-beta1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was approximately 6-fold elevated in Ang II-treated wild-type, but not TGF-beta1-deficient mice. However, the alpha- to beta-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-beta1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-beta1 is an important mediator of the hypertrophic growth response of the heart to Ang II.
Schultz
Jo El J
Jel J
Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, OH 45267, USA. schuljo@email.uc.edu
Witt
Sandra A
SA
Glascock
Betty J
BJ
Nieman
Michelle L
ML
Reiser
Peter J
PJ
Nix
Stacey L
SL
Kimball
Thomas R
TR
Doetschman
Thomas
T
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D048429:Cell Size; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D018995:Myosin Heavy Chains