Journal
CARDIOVASCULAR RESEARCH
Volume 85, Issue 3, Pages 514-519Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvp337
Keywords
Endothelial; Vascular; SIRT1; Resveratrol; Kruppel-like factor 2
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Funding
- National Institutes of Health [HL-076686, HL-090856]
- Department of Innovation, Universities and Enterprise, Government of Catalonia, Spain [BP-A 00137]
- Howard Hughes Medical Institute
- American Federation for Aging Research/National Institute on Aging [AG026781]
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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 Kruppel-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.
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