SIRT1 in athero-thrombosis
SIRT1 is the best characterized member of the class III (histone) deacetylases (HDAC), and its role has been implicated in various molecular and physiological processes. Together with colleagues we demonstrated that SIRT1 exerts atheroprotective functions in macrophages and vascular endothelial cells. Using genetic loss- and gain-of-function approaches, we showed that SIRT1 reduces the expression of Lox-1 via suppression of NF-κB signaling in macrophages (Stein, 2010b). Bone-marrow transplantations demonstrated that macrophage-derived SIRT1 is sufficient to decrease atherogenesis (Stein, 2010b). In two further studies, we showed that suppression of NF-κB signaling by SIRT1 in endothelial cells diminishes the expression of pro-inflammatory adhesion molecules, thereby preventing endothelial activation (Stein, 2010c) and reducing the expression of tissue factor, a key factor in the activation of the coagulation cascade during arteriothrombosis (Breitenstein, 2011). Taken together, our data showed that SIRT1 prevents atherosclerosis in early and advanced stages (Stein, 2011; Winnik, 2012).
Crosssection of an aortic plaque in mice. Green, endothelial cells; red, macrophages.
Using a pharmacological approach, we demonstrated that the SIRT1 activator SRT3025 protects mice against atherosclerosis development by reducing hepatic PCSK9 secretion and increasing hepatic LDLR expression (Miranda, 2014). Thus, the availability of specific SIRT1-activating drugs suggests that pharmacological activation of SIRT1 may become an attractive anti-atherogenic strategy.
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