Cardiovascular Research Advance Access first published online on October 8, 2009
This version [Corrected Proof] published online on November 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp337
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Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype
1 Laboratory for Systems Biology, Departments of Pathology, Center for Excellence in Vascular Biology, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB-730C, Boston, MA 02115, USA
2 Harvard-MIT Division of Health, Sciences, and Technology, Harvard Medical School, Boston, MA 02115, USA
* Corresponding author. Tel: +1 617 525 4302, Fax: +1 617 525 4329, Email: guillermo_garcia-cardena{at}hms.harvard.edu
Aims: Resveratrol activates Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase which modulates metabolic homeostasis and improves several pathophysiological features present in diseases of ageing. In particular, it has been shown that SIRT1 activation improves endothelial dysfunction and suppresses vascular inflammation, two central pathophysiological processes involved in the initiation and progression of cardiovascular disease. The downstream targets of SIRT1 activation in this context, however, remain poorly defined. Therefore, in this study, we aimed to characterize mechanistically how SIRT1 activation regulates the endothelial vasoprotective phenotype.
Methods and results: We demonstrate that SIRT1 activation by resveratrol increases the expression of the transcription factor Krüppel-like factor 2 (KLF2) in human vascular endothelial cells, resulting in the orchestrated regulation of transcriptional programs critical for conferring an endothelial vasoprotective phenotype. Moreover, we show that KLF2 upregulation by resveratrol occurs via a mitogen-activated protein kinase 5/myocyte enhancing factor 2-dependent signalling pathway.
Conclusion: Collectively, these observations provide a new mechanistic framework to understand the vascular protective effects mediated by SIRT1 activators and define KLF2 as a critical mediator of these effects.
KEYWORDS Endothelial; Vascular; SIRT1; Resveratrol; Krüppel-like factor 2
Time for primary review: 10 days
The first two authors contributed equally to the study.