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Cardiac Myocyte-specific Ablation of Follistatin-like 3 Attenuates Stress-induced Myocardial Hypertrophy

J. Biol. Chem., 18 March 2011
Vol. 286, Issue 11, p. 9840-9848
DOI: 10.1074/jbc.M110.197079

Cardiac Myocyte-specific Ablation of Follistatin-like 3 Attenuates Stress-induced Myocardial Hypertrophy

  1. Masayuki Shimano,1,
  2. Noriyuki Ouchi,
  3. Kazuto Nakamura,
  4. Yuichi Oshima,
  5. Akiko Higuchi,
  6. David R. Pimentel,
  7. Kalyani D. Panse§,
  8. Enrique Lara-Pezzi,
  9. Se-Jin Lee,
  10. Flora Sam and
  11. Kenneth Walsh,2
  1. From the Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, Massachusetts 02118,
  2. the §Heart Science Centre, Imperial College London, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom,
  3. the Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernandez Almagro 3, Madrid 28029, Spain, and
  4. the Department of Molecular Biology and Genetics, The Johns Hopkins University, Baltimore, Maryland 21205
  1. 2 To whom correspondence should be addressed: Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University Medical Campus, 700 Albany St., W611, Boston, MA 02118. Tel.: 617-414-2390; Fax: 617-414-2391; E-mail: kxwalsh{at}bu.edu.

Abstract

Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 3 (Fstl3) is an extracellular regulator of certain TGF-β family members, including activin A. The aim of this study was to examine the role of Fstl3 in cardiac hypertrophy. Cardiac myocyte-specific Fstl3 knock-out (KO) mice and control mice were subjected to pressure overload induced by transverse aortic constriction (TAC). Cardiac hypertrophy was assessed by echocardiography and histological and biochemical methods. KO mice showed reduced cardiac hypertrophy, pulmonary congestion, concentric LV wall thickness, LV dilatation, and LV systolic dysfunction after TAC compared with control mice. KO mice displayed attenuated increases in cardiomyocyte cell surface area and interstitial fibrosis following pressure overload. Although activin A was similarly up-regulated in KO and control mice after TAC, a significant increase in Smad2 phosphorylation only occurred in KO mice. Knockdown of Fstl3 in cultured cardiomyocytes inhibited PE-induced cardiac hypertrophy. Conversely, adenovirus-mediated Fstl3 overexpression blocked the inhibitory action of activin A on hypertrophy and Smad2 activation. Transduction with Smad7, a negative regulator of Smad2 signaling, blocked the antihypertrophic actions of activin A stimulation or Fstl3 ablation. These findings identify Fstl3 as a stress-induced regulator of hypertrophy that controls myocyte size via regulation of Smad signaling.

  • Cardiac Hypertrophy
  • Heart
  • Signal Transduction
  • Smad Transcription Factor
  • Transforming Growth Factor-β (TGF-β)
  • Follistatin-like 3
  • Activin A
  • Cardiomyokine
  • Heart Failure
  • Myocytes

Footnotes

  • 1 Supported by the Banyu Fellowship Program sponsored by Banyu Life Science Foundation International.

  • * This work was supported, in whole or in part, by National Institutes of Health Grants AG015052, AG034972, HL068758, HL102874, and DK089875 (to K. W.) and AR060636 (to S.-J. L.).

  • Embedded Image The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

  • Received October 22, 2010.
  • Revision received December 22, 2010.

Citation:

M. Shimano, N. Ouchi, K. Nakamura, Y. Oshima, A. Higuchi, D. R. Pimentel, K. D. Panse, E. Lara-Pezzi, S.-J. Lee, F. Sam, and K. Walsh, Cardiac Myocyte-specific Ablation of Follistatin-like 3 Attenuates Stress-induced Myocardial Hypertrophy. J. Biol. Chem. 286, 9840-9848 (2011).

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