Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on August 30, 2004
Revised on November 15, 2004
Accepted on November 23, 2004

Serum and Glucocorticoid-Responsive Kinase-1 Regulates Cardiomyocyte Survival and Hypertrophic Response

Takuma Aoyama MD, PhD, Takashi Matsui MD, PhD, Mikhail Novikov MD, Jongsun Park PhD, Brian Hemmings PhD, and Anthony Rosenzweig MD^*

From the Program in Cardiovascular Gene Therapy and Cardiology Division, MGH, Harvard Medical School, Boston, Mass (T.A., T.M., M.N., A.R.), and Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland (J.P., B.H.).

^* To whom correspondence should be addressed. E-mail: arosenzweig{at}partners.org.

Background--Serum- and glucocorticoid-responsive kinase-1 (SGK1), a serine-threonine kinase that is highly expressed in the heart, has been previously reported to regulate sodium channels. Because SGK1 is a PI 3-kinase-dependent kinase with structural homology to Akt, we examined its regulation in the heart and its effects on cardiomyocyte (CM) apoptosis and hypertrophy in vitro.

Methods and Results--Rats were subjected to aortic banding, and expression of total and phosphorylated SGK1 was examined. Both phospho- and total SGK1 increased 2 to 7 days after banding. Phospho-SGK1 was also upregulated in CMs stimulated in vitro with IGF-I or phenylephrine. Infection of CMs with an adenoviral vector encoding constitutively active SGK1 (Ad.SGK1.CA) inhibited apoptosis after serum-deprivation or hypoxia (P<0.05), whereas expression of kinase-dead SGK1 (Ad.SGK1.KD) increased it and partially mitigated the protective effects of IGF-I (P<0.05). SGK1 activation was also sufficient to increase cell size, protein synthesis, sarcomere organization, and ANF expression both at baseline and in response to phenylephrine but was not necessary for the hypertrophic response to phenylephrine. Evaluation of potential downstream signaling pathways demonstrated that SGK1 induces phosphorylation of tuberin, p70s6kinase, and GSK3 in CMs, which may contribute to its effects.

Conclusions--SGK1 is dynamically regulated during acute biomechanical stress in the heart and inhibits CM apoptosis while enhancing the hypertrophic response.

Key words: apoptosis • hypertrophy • signal transduction

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