Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm
Open accessAbstract
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 AAA-related 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. Conclusions: These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.
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Senescence-associated markers have been identified in atherosclerosis, abdominal aortic aneurysm, and thoracic aortic aneurysm in human and mouse models.
“Senescence-associated markers have also been identified in the context of vascular diseases such as atherosclerosis and abdominal aortic aneurysm and thoracic aortic aneurysm in both human and mouse models69–72.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [70]
Senescent cardiovascular cells specifically contribute to chronic cardiovascular diseases, including atherosclerosis, abdominal aortic aneurysm, thoracic aortic aneurysm, artery stiffness and heart failure.
“Senescent cardiovascular cells specifically contributes to chronic CVD, including atherosclerosis [47], abdominal aortic aneurysm (AAA) [48], thoracic aortic aneurysm (TAA) [49], artery stiffness [50] and heart failure [51].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [48]
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- Authors
- Chen, H.-Z., Wang, F., Gao, P., Pei, J.-F., Liu, Y., Xu, T.-T., Tang, X., Fu, W.-Y., Lu, J., Yan, Y.-F., Wang, X.-M., Han, L., Zhang, Z.-Q., Zhang, R., Zou, M.-H., & Liu, D.-P.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
- Corresponding author
- Chen, Hou-Zao
- Wang, Fang
- Gao, Peng
- Pei, Jian-Fei
- ORCID
- Venue
- Circulation Research
- Published
- 2016-10-28
- Volume
- 119
- Issue
- 10
- Pages
- 1076-1088
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6546422
- OpenAlex
- W2522551629
- Cited by
- 265
- References
- 43
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 25 · 2023: 30 · 2022: 43 · 2021: 38 · 2020: 36 · 2019: 12 · 2018: 19 · 2017: 13 · 2016: 2
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG047776)
- National Heart, Lung, and Blood Institute (R01HL105157, R01HL079584, R01HL142287, R01HL137371, R01HL132500, R01HL074399, R01HL080499, R01HL140954, R01HL110488, R01HL128014, R01HL089920, R01HL096032)
- National Cancer Institute (R01CA213022)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic aneurysm repair treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Keywords
- SIRT1, abdominal aortic aneurysm, vascular smooth muscle cells, vascular aging, vascular inflammation, aging, angiotensin II, p21, NF-κB, MCP-1, histone deacetylase, aneurysm formation, aneurysm rupture, ApoE-deficient mice
- MeSH terms
- Aging, Angiotensin II, Animals, Aortitis, Apolipoproteins E, Calcium Chloride, Disease Models, Animal, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular, NF-kappa B, Aneurysm, Ruptured, Aortic Aneurysm, Abdominal, Mice, Knockout, Chemokine CCL2, Mice, Sirtuin 1
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