TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II
Jo El J. Schultz, … , Thomas R. Kimball, Thomas Doetschman
Jo El J. Schultz, … , Thomas R. Kimball, Thomas Doetschman
Published March 15, 2002
Citation Information: J Clin Invest. 2002;109(6):787-796. https://doi.org/10.1172/JCI14190.
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Article

TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II

Abstract

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-β1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-β1–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 IItreatment. 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-β1–deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II–treated mice. Atrial natriuretic factor expression was ∼6-fold elevated in Ang II–treated wild-type, but not TGF-β1–deficient mice. However, the α- to β-myosin heavy chain switch did not occur in Ang II–treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-β1. The Ang IIeffect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-β1 is an important mediator of the hypertrophic growth response of the heart to Ang II.

Authors

Jo El J. Schultz, Sandra A. Witt, Betty J. Glascock, Michelle L. Nieman, Peter J. Reiser, Stacey L. Nix, Thomas R. Kimball, Thomas Doetschman

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Tissue weight-to-tibia length ratios for 4-week saline- and Ang II–treat...
Tissue weight-to-tibia length ratios for 4-week saline- and Ang II–treated Tgfb1+/+Rag1–/– and Tgfb1–/–Rag1–/– mice. All values are expressed as mean ± SEM. *P < 0.05 vs. saline treatment. n = 8 for saline-treated Tgfb1+/+Rag1–/– mice, and n = 6 for saline-treated Tgfb1–/–Rag1–/– mice. n = 11 for Ang II–treated Tgfb1+/+Rag1–/– mice, and n = 10 for Ang II–treated Tgfb1–/–Rag1–/– mice. (a) Ang II–treated Tgfb1+/+Rag1–/– mice (white bars) had a significant increase in heart/tibia ratio compared with the saline-treated mice (dark gray bars). (b) No significant difference in heart/tibia was observed in 4-week saline-treated (light gray bars) and Ang II–treated Tgfb1–/–Rag1–/– mice (black bars). Inset: Graph depicting changes in body weight (small symbols) and tibia length (large symbols) in saline- and Ang II–treated Tgfb1+/+Rag1–/– and Tgfb1–/–Rag1–/– mice. Saline-treated Tgfb1+/+Rag1–/– mice, filled diamonds. Saline-treated Tgfb1–/–Rag1–/– mice, open squares. Ang II–treated Tgfb1+/+Rag1–/– mice, open diamonds. Ang II–treated Tgfb1–/–Rag1–/– mice, filled squares. Body weight was significantly lower in Tgfb1–/–Rag1–/– mice compared with Tgfb1+/+Rag1–/– mice and continued to decrease during the course of the study, whereas tibia length for both groups of mice was similar.