sirt1 inhibits resistin expression in aortic stenosis在主动脉瓣狭窄sirt1抑制抵抗素的表达.pdfVIP

Sirt1 Inhibits Resistin Expression in Aortic Stenosis ´ Sophie Carter, Stephanie Miard, Catherine Roy-Bellavance, Louise Boivin, Zhuo Li, Philippe Pibarot, ´ ´ Patrick Mathieu, Frederic Picard* ´ ´ Quebec Heart and Lung Research Center, Laval University, Quebec, Quebec City, Canada Abstract The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro- inflammatory cytokines, including resistin. However, the molecular mechanisms contributing to these processes are not established. Since Sirt1 has been shown to modulate macrophage biology and inflammation, we examined its levels in human AS and tested its impact on resistin expression. Sirt1 mRNA (p = 0.01) and protein (p,0.05) levels were reduced in explanted valves from AS patients (n = 51) compared to those from control (n = 11) patients. Sirt1 mRNA levels were negatively associated with resistin mRNA levels quantified in AS valves (p = 0.02). Stimulation of Sirt1 by resveratrol or virus- driven overexpression robustly diminished resistin mRNA and protein expression in macrophages, whereas down-regulation of Sirt1 triggered a large increase in resistin expression. These effects were direct, as chromatin immunoprecipitation assays showed that Sirt1 physically interacted with the resistin promoter region at an AP-1 response element. Moreover, Sirt1 blocked c-jun-induced resistin transactivation in gene reporter assays. These findings demonstrate that, in calcified AS, levels of Sirt1 ar