Rationale: Inactivation of the p66Shc adaptor protein confers resistance to oxidative stress and protects mice from aging-associated vascular diseases. However, there is limited information about the negative regulating mechanisms of p66Shc expression in the vascular system. Objective:In this study, we investigated the role of SIRT1, a class III histone deacetylase, in the regulation of p66Shc expression and hyperglycemia-induced endothelial dysfunction. Methods and Results:Expressions of p66Shc gene transcript and protein were significantly increased by different kinds of class III histone deacetylase (sirtuin) inhibitors in human umbilical vein endothelial cells and 293A cells. Adenoviral overexpression of SIRT1 inhibited high-glucose-induced p66Shc upregulation in human umbilical vein endothelial cells. Knockdown of SIRT1 increased p66Shc expression and also increased the expression levels of plasminogen activator inhibitor-1 expression, but decreased manganese superoxide dismutase expression in high-glucose conditions. However, knockdown of p66Shc significantly reversed the effects of SIRT1 knockdown. In addition, p66Shc overexpression significantly decreased manganese superoxide dismutase expression and increased plasminogen activator inhibitor-1 expression in high-glucose conditions, which were recovered by SIRT1 overexpression. Moreover, compared to streptozotocin-induced wild-type diabetic mice, endothelium-specific SIRT1 transgenic diabetic mice had decreased p66Shc expression at both the mRNA and the protein levels, improved endothelial function, and reduced accumulation of nitrotyrosine and 8-OHdG (markers of oxidative stress). We further found that SIRT1 was able to bind to the p66Shc promoter (؊508 bp to ؊250 bp), resulting in a decrease in the acetylation of histone H3 bound to the p66Shc promoter region. Conclusion:

Background Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. Methods Male C57BL/6J wild-type (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/day for four weeks) in male C57BL/6J Sirt2-KO mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice and their respective littermates (8~12-week-old). Metformin (200 mg/kg/day) was used to treat WT and Sirt2-KO mice that were infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results SIRT2 protein expression levels were down-regulated in hypertrophic hearts from mice. Sirt2-KO markedly exaggerated cardiac hypertrophy and fibrosis as well as decreases in cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. Conclusions SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

A bdominal aortic aneurysms (AAAs), characterized by a permanent, localized dilatation (ballooning) of the abdominal aorta that exceeds the normal diameter by >50%, are the most common form of aortic aneurysm. AAA rupture and the associated catastrophic physiological insult carry an overall mortality rate in excess of 80%; ruptured AAAs are the 13th leading cause of death in the United States.1,2 Pathologically, AAAs are characterized by increased inflammatory cell infiltration, aberrant oxidant stress, medial elastin degradation, and medial collagen deposition. Apart from surgery, few medical treatments have been shown to prevent AAA development and growth, 3,4 primarily as a result of the limited understanding of its pathogenic mechanisms.AAAs are found in up to 8% of men aged >65 years. AAA incidence increases steeply by 40% every 5 years in men who Molecular Medicine© 2016 American Heart Association, Inc. Rationale: Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown.Objective: In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation. Methods and Results:The expression and activity of SIRT1 were significantly decreased in human AAA samples.SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell-specific knockout of SIRT1 accelerated angiotensin II-induced formation and rupture of AAAs and AAArelated pathological changes, whereas vascular smooth muscle cell-specific overexpression of SIRT1 suppressed angiotensin II-induced AAA formation and progression in Apoe −/− mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl 2 )-induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II-induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression. Chen et al Conclusions: SIRT1 Reduction Promotes AAAs 1077are >65 years old, indicating that age is a major risk factor for AAAs.2 Although age-related alterations such as enhanced inflammatory responses, vascular stiffening, and oxidative stress make aged arteries more susceptible to vascular diseases, such as atherosclerosis, 5-7 the reasons why AAAs are often observed in patients with advanced age (>65 years) and how advanced age dramatically accelerates the development and progression of aneurysms in abdominal ...

SIRT1 (Sirtuin type 1), a mammalian orthologue of yeast SIR2 (silent information regulator 2), has been shown to mediate a variety of calorie restriction (CR)-induced physiological events, such as cell fate regulation via deacetylation of the substrate proteins. However, whether SIRT1 deacetylates activator protein-1 (AP-1) to influence its transcriptional activity and target gene expression is still unknown. Here we demonstrate that SIRT1 directly interacts with the basic leucine zipper domains of c-Fos and c-Jun, the major components of AP-1, by which SIRT1 suppressed the transcriptional activity of AP-1. This process requires the deacetylase activity of SIRT1. Notably, SIRT1 reduced the expression of COX-2, a typical AP-1 target gene, and decreased prostaglandin E 2 (PGE 2 ) production of peritoneal macrophages (pM⌽s). pM⌽s with SIRT1 overexpression displayed improved phagocytosis and tumoricidal functions, which are associated with depressed PGE 2 . Furthermore, SIRT1 protein level was up-regulated in CR mouse pM⌽s, whereas elevated SIRT1 decreased COX-2 expression and improved PGE 2 -related macrophage functions that were reversed following inhibition of SIRT1 deacetylase activity. Thus, our results indicate that SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function.