Cardiac Physiology

Limiting Heart Hypertrophy

Science Signaling  22 Mar 2011:
Vol. 4, Issue 165, pp. ec88
DOI: 10.1126/scisignal.4165ec88

In response to cardiac stress, the heart undergoes adaptive hypertrophy. Unfortunately, long-term sustained hypertrophy can ultimately compromise heart function. Members of the transforming growth factor–β (TGF-β) family can either inhibit or promote growth by signaling through specific Smad proteins, which are transcriptional regulators. TGF-β family members activin A and myostatin, which are antagonized by follistatin and the heart-expressed follistatin-like 3 (Fstl3), inhibit cardiac cell hypertrophy in vitro. Because the abundance of Fstl3 transcripts is increased in cardiac myocytes of patients with end-stage heart failure and its abundance is correlated with disease severity, Shimano et al. created knockout mice lacking Fstl3 in cardiac myocytes and showed that, in response to pressure overload, the knockout mice exhibited less cardiac hypertrophic response than did control mice based on morphological, histological, and echocardiographic analysis. After pressure overload, the hearts of Fstl3-knockout mice exhibited increased Smad2 phosphorylation (an indication of active Smad2) but not an increase in the activity of other Smads (Smad1, 5, 4, or 6). To investigate the molecular pathway through which Fstl3 acted, the authors examined cultured neonatal rat ventricular myocytes, which undergo hypertrophy in response to the adrenergic receptor agonist phenylephrine. The abundances of activin A and Fstl3 were increased at the transcript and protein level after phenylephrine stimulation. After phenylephrine stimulation, the cardiac myocytes deficient in Fstl3 (through knockdown) exhibited a reduced hypertrophic response; Smad2 phosphorylation was increased, and cell surface area, protein synthesis, and the induction of specific transcripts associated with hypertrophy were reduced. In contrast, Fstl3-knockdown cells did not exhibit differences from control cardiac myocytes in the absence of phenylephrine. Overexpression of Smad7, an inhibitor of Smad2, or treatment of the cardiomyocyte cultures with an inhibitor of the TGF-β receptors ALK4, 5, and 7 prevented the inhibitory effects of Fstl3 knockdown on phenylephrine-induced hypertrophy. Overexpression of activin A reduced the hypertrophic response induced by phenylephrine, and Fstl3 overexpression prevented this effect of activin A. These studies suggest that, by inhibiting activin A, Fstl3 promotes the hypertrophic response in cardiac myocytes.

M. Shimano, N. Ouchi, K. Nakamura, Y. Oshima, A. Higuchi, D. R. Pimentel, K. D. Panse, E. Lara-Pezzi, S.-J. Lee, F. Sam, K. Walsh, Cardiac myocyte-specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy. J. Biol. Chem. 286, 9840–9848 (2011). [Abstract] [Full Text]