Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Gracia-Sancho
Jorge
J
Laboratory for Systems Biology, Department 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.
Villarreal
Guadalupe
G
Zhang
Yuzhi
Y
García-Cardeña
Guillermo
G
D000263:Adenylate Kinase / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D026161:MADS Domain Proteins / Q000502:physiology; D048671:MAP Kinase Kinase 5 / Q000502:physiology; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology; D018006:Myogenic Regulatory Factors / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010641:Phenotype; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*
C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D013267:Stilbenes; D052250:Nitric Oxide Synthase Type III; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D000263:Adenylate Kinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol