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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Figure 1

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Serial echocardiographic results for Tgfb1+/+Rag1–/– and Tgfb1–/–Rag1–/–...
Serial echocardiographic results for Tgfb1+/+Rag1–/– and Tgfb1–/–Rag1–/– mice before and weeks during saline or subpressor Ang II treatment. LV mass was estimated from the echocardiographic measurements of SWT, PWT, and LVED. All values are expressed as mean ± SEM. *P < 0.05 vs. pre-Ang II. #P < 0.05 vs. Tgfb1+/+Rag1–/–. 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 Ang II–treated Tgfb1–/–Rag1–/– mice. (a) Estimated LV mass for pretreatment and 1–4 weeks of saline-treated (dark gray bars) or Ang II–treated (white bars) Tgfb1+/+Rag1–/– mice. By 3 weeks of subpressor Ang II treatment, a marked increase in LV mass was observed in Tgfb1+/+Rag1–/– mice compared with their saline cohorts. (b) Estimated LV mass for pretreatment and 1–4 weeks of saline-treated (light gray bars) or Ang II–treated (black bars) Tgfb1–/–Rag1–/– mice. No significant increase in LV mass was noted in Ang II–treated Tgfb1–/–Rag1–/– mice compared with their saline cohorts.