The sirtuin SIRT1 is an ubiquitous NAD(+) dependent deacetylase that plays a role in biological processes such as longevity and stress response. In cardiac models, SIRT1 is associated to protection against many stresses. However, the link between SIRT1 and heart hypertrophy is complex and not fully understood. This study focuses specifically on the response of SIRT1 to the alpha-adrenergic agonist phenylephrine in H9c2 cardiac myoblasts, a cell model of cardiac hypertrophy. After 24 and 48 h of phenylephrine treatment, SIRT1 expression and deacetylase activity were significantly increased. SIRT1 upregulation by phenylephrine was not associated to changes in NAD(+) levels, but was blocked by inhibitors of AMP-activated Protein Kinase (AMPK) or by AMPK knockdown by siRNA. When SIRT1 was inhibited with sirtinol or downregulated by siRNA, H9c2 cell viability was significantly decreased following phenylephrine treatment, showing that SIRT1 improves cell survival under hypertrophic stress. We so then propose that the increase in SIRT1 activity and expression in H9c2 cells treated with phenylephrine is an adaptive response to the hypertrophic stress, suggesting that adrenergic stimulation of heart cells activates hypertrophic programming and at the same time also promotes a self-protecting and self-regulating mechanism. (C) 2011 Elsevier Inc. All rights reserved.