Al Sayah, Leona2016-06-282016https://hdl.handle.net/2144/16747BACKGROUND: Arterial stiffness, or the loss of compliance of the large arteries, is a major independent predictor of cardiovascular events. Obesity induced by a high fat, high sucrose (HFHS) diet, in mice, causes the development of arterial stiffness, diabetes, and hypertension. Along with the resulting metabolic syndrome, inflammation and oxidants are increased in vascular smooth muscle (VSM) cells of HFHS-fed mice. Sirtuin 1 (SirT1), an important cellular homeostatic regulator, has been shown to prevent inflammation and obesity-associated metabolic impairment in animal models. This deacetylase is involved in histone and transcription factor regulation, thereby affecting a wide range of physiological mechanisms. However, whether SirT1 affects obesity-induced arterial stiffness is unknown. Therefore, we aimed to investigate the effects of SirT1 on arterial stiffening in a setting of diet-induced obesity. METHODS: The polyphenolic SirT1 activators, resveratrol and S17834, were added to HFHS diet fed to WT mice for 8 months. Arterial stiffness was measured in vivo, by pulse wave velocity (PWV), at baseline, 4 months, and 8 months. In another experiment, a highly selective SirT1 activator, SRT1720, was administered to mice in HFHS diet for one week following 8 months of HFHS diet, and PWV was measured before and after treatment. To study the role of VSM SirT1 in HFHS-induced arterial stiffness, resveratrol was supplemented to HFHS diet-fed mice lacking SirT1 in VSM (SMKO), and PWV was measured in comparison to control HFHS-fed mice. Additionally, mice overexpressing SirT1 in VSM specifically (SMTG) were generated and placed on HFHS diet, and PWV was measured at baseline, 4 months, and 8 months. The effects of SirT1 on oxidant production and inflammation in the different experimental groups were assessed by staining aortic sections for oxidants and performing Western blots of inflammatory markers (phospho-p65 NFκB, VCAM1) on isolated aortic and VSM cell lysates. RESULTS: Administering resveratrol and S17834 completely prevented the development HFHS-induced arterial stiffness over 8 months. Similarly, elevated PWV due to 8 months of HFHS diet was reversed by one-week treatment with SRT1720. SirT1 knockout in VSM partially prevented resveratrol’s effect in lowering arterial stiffness. Mice overexpressing SirT1 in VSM (SMTG) did not develop arterial stiffness and were protected from HFHS-induced oxidant production and inflammation (upregulation of phospho-p65 NFκB and VCAM1). CONCLUSIONS: VSM SirT1 can prevent the development of arterial stiffness in settings of obesity by opposing oxidants and inflammation in the aortic wall. SirT1 activators represent a potential therapeutic approach to alleviate the burden of cardiovascular disease in obese individuals with metabolic syndrome.en-USHealth sciencesThesis/Dissertation2016-06-17