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 ...
