SIRT1 - An Anti-Inflammatory Pathway at the Crossroads Between Metabolic Disease and Atherosclerosis

Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis.