Original ArticleHigh-fat Diet Increases and the Polyphenol, S17834, Decreases Acetylation of the Sirtuin-1–dependent Lysine-382 on p53 and Apoptotic Signaling in Atherosclerotic Lesion–prone Aortic Endothelium of Normal MiceXu, Shanqin MS*; Jiang, Bingbing PhD*; Hou, Xiuyun MS*; Shi, Chaomei MS*; Bachschmid, Markus M PhD*; Zang, Mengwei PhD*; Verbeuren, Tony J PhD†; Cohen, Richard A MD*Author Information From the *Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; and †Division of Angiology, Institut de Recherche Servier, Suresnes, France. Received for publication January 14, 2011; accepted May 9, 2011. Supported by a Strategic Alliance between the Vascular Biology Section at Boston University Medical Center and the Institut de Recherche Servier; and by the National Institutes of Health Grants (P01-HL068758, R37-HL104017 and R01 DK076942), by the National Heart, Lung, and Blood Institute Proteomics Initiative, contract no. HHSN268201000031C, and by an ARCaward from the Evans Center for Interdisciplinary Research at Boston University. T.J. Verbeuren is an employee and R.A. Cohen is a consultant to Institut de Recherche Servier. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Reprints: Richard A. Cohen, MD, Vascular Biology Unit, X720, Boston University Medical Center, 650 Albany St, Boston 02118, MA (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: September 2011 - Volume 58 - Issue 3 - p 263-271 doi: 10.1097/FJC.0b013e3182239eb7 Buy SDC Metrics Abstract Our purpose was to determine if high-fat diet and treatment with a polyphenol regulate the acetylation of lysine-382 of p53, the site regulated by sirtuin-1, and apoptosis in the endothelium of the atherosclerotic lesion-prone mouse aortic arch. In cultured endothelial cells, 2 atherogenic stimuli, hydrogen peroxide and tumor necrosis factor-α, increased the acetylation of p53 lysine-382, and caspase-3 cleavage, an indicator of apoptotic signaling. The polyphenol, S17834, significantly prevented these changes. In low-density lipoprotein receptor-deficient mice, a high-fat diet increased, and treatment with S17834 attenuated early atherosclerotic lesions on the lesser curvature of the aortic arch. In wild-type C57BL6 mice fed the same diet, no atherosclerotic lesions were observed in this lesion-prone area, but p53 acetylation and caspase-3 cleavage increased in the endothelium. In high-fat fed mice, S17834 increased sirtuin-1 protein in the lesion-prone endothelium and prevented both the increase in p53 acetylation and caspase-3 cleavage without affecting blood lipids. These results indicate that high-fat diet increases and S17834 decreases the acetylation of p53 in lesion-prone aortic endothelial cells of normal mice independently of blood lipids, suggesting that the polyphenol may regulate endothelial cell p53 acetylation and apoptosis via local actions. © 2011 Lippincott Williams & Wilkins, Inc.