Gracia-Sancho Jorge, Villarreal Guadalupe, Zhang Yuzhi, García-Cardeña Guillermo
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.
Cardiovasc Res. 2010 Feb 1;85(3):514-9. doi: 10.1093/cvr/cvp337. Epub 2009 Oct 8.
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.
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.
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.
白藜芦醇可激活沉默调节蛋白1（SIRT1），这是一种烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶，可调节代谢稳态，并改善衰老相关疾病中存在的多种病理生理特征。特别是，研究表明SIRT1激活可改善内皮功能障碍并抑制血管炎症，这是心血管疾病发生和发展过程中的两个核心病理生理过程。然而，在此背景下，SIRT1激活的下游靶点仍不清楚。因此，在本研究中，我们旨在从机制上描述SIRT1激活如何调节内皮血管保护表型。
我们证明，白藜芦醇激活SIRT1可增加人血管内皮细胞中转录因子Krüppel样因子2（KLF2）的表达，从而对赋予内皮血管保护表型至关重要的转录程序进行协调调控。此外，我们表明，白藜芦醇上调KLF2是通过丝裂原活化蛋白激酶5/心肌细胞增强因子2依赖性信号通路实现的。
总的来说，这些观察结果提供了一个新的机制框架，以理解SIRT1激活剂介导的血管保护作用，并将KLF2定义为这些作用的关键介质。
