Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta with over 85% mortality after rupture. Currently, there are no therapeutic strategies proven to blunt AAA progression and rapture, making surgery as the only available option. Human epidemiologic data indicates that aging is a major risk factor in AAAs. As the population lives longer, it is anticipated that AAA incidence will become even more prevalent. The rising prevalence of AAAs, coupled with the high mortality from ruptured AAA, clearly supports the need for research to define mechanisms of AAA formation and progression. Despite that advanced age is a known major risk factor for AAA, the molecular basis underlying aging-accelerated AAA formation remains largely unknown. We have obtained exciting preliminary data showing that age- associated inhibition of Sirt1 (an NAD+-dependent deacetylase) in vascular smooth muscle cells (VSMCs) of suprarenal aortas accentuates Ang II-triggered AAAs. Further, infusion of angiotensin (Ang) II, a well-characterized mouse model of AAA, significantly lowered Sirt1 activity. Moreover, the formation and rupture of AAAs in response to Ang II were accelerated in Sirt1-VSMC-specific knockout (SV-KO) mice. Concomitantly, we found vascular aging markers [p21, p53, and Senescence Associated ?-galactosidase (SA-?-gal)-positive staining)] were significantly elevated in the aortas of SV-KO mice but were reduced in those from SV-Tg mice. Finally, we found that Sirt1 ablation increased the protein and mRNA level of matrix metalloproteinases (MMP) 2 and MT1-MMP after Ang II treatment. Mechanically, we found that increased levels of p21 in old aortas significantly enhance the binding of AP2?, a transcriptional factor activated by Ang II, to the MMP2 promoter resulting in aberrant expression of MMP2. Thus, our central hypothesis is that oxidative inactivation of Sirt1 in aged aortas increases p53/p21, which exacerbates Ang II-induced AP2?-mediated MMP2 expression in VSMCs and aneurysm. To validate or refute this hypothesis, we propose the following specific aims: (1) determine the effects of advanced age or Ang II infusion on Sirt1 activity and evaluate if Sirt1 reduction causes premature vascular aging in mouse in vivo;(2) establish that age-related Sirt1 reduction accelerates Ang II-instigated destruction of the vessel wall and aneurysm formation in mice in vivo;and (3) elucidate how Sirt1 inactivation accelerates AAA. This application has high clinically innovations and significance because we anticipate that the completion of this application will help identify Sirt1 activation as a novel potential therapeutic target for preventing AAA initiation, progression, and rapture in patients with advanced ages.
Human epidemiologic data indicates that age is a major risk factor for AAAs. In this application, a combination of pharmacological, molecular, and genetic means with gain- of-function and loss-of-function approaches will be used to dissect why Sirt1 inhibition by advanced age (>65 years) precipitates AAA development and progression.
|Wang, Qiongxin; Zhang, Miao; Ding, Ye et al. (2014) Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circ Res 114:480-92|
|Okon, Imoh S; Coughlan, Kathleen A; Zhang, Cheng et al. (2014) Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J Clin Invest 124:4590-602|
|Shirwany, Najeeb A; Zou, Ming-Hui (2014) AMPK: a cellular metabolic and redox sensor. A minireview. Front Biosci (Landmark Ed) 19:447-74|