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Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells

Acta Pharmacologica Sinica volume 47, pages 103–118 (2026)Cite this article

Abstract

Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.

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Fig. 1: SIRT6 expression was decreased in vascular smooth muscle cells of AAD.
Fig. 2: VSMC-specific SIRT6 deficiency promoted AAD formation in mice.
Fig. 3: VSMC-specific SIRT6 deficiency aggravated Ang II-induced vascular fibrosis and elastic fiber rupture.
Fig. 4: VSMC-specific SIRT6 deficiency increased Ang II-induced VSMC apoptosis and senescence.
Fig. 5: VSMC-specific SIRT6 deficiency perturbed mitochondrial complex and function in AAD.
Fig. 6: SIRT6 knockdown impaired mitochondrial structure and function in vitro.
Fig. 7: SIRT6 interacted with NRF2 by its deacetylase activity to protect against mitochondria dysfunction.
Fig. 8: SIRT6 agonist MDL-811 improves AAD in vivo and in vitro.
Fig. 9: Vascular smooth muscle cell SIRT6 protects against aortic aneurysm and dissection.

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Acknowledgements

This study was supported by National Key R&D Program of China (2021YFA080021), National Natural Science Foundation of China (92368106), and the National Cancer Institute Intramural Research Program (ZIABC005562). We thank Prof. Jian Zhang for generously providing the SIRT6 agonist MDL-811 and Prof. Jin-han He for providing Sirt6-floxed mice.

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Author notes

  1. These authors contributed equally: Xiao-ting Yu, Nan Zhao

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China

    Xiao-ting Yu, Nan Zhao, Yu-tao Ma, Yao Xiao & Ai-juan Qu

  2. Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Xiao-ting Yu, Xiao-yan Liu & Frank J. Gonzalez

  3. MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST/Department of Automation, Tsinghua University, Beijing, 100084, China

    Jin-meng Jia

  4. Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Yan-ting Song

  5. Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Bo Jia & Jun-ming Zhu

  6. Beijing You-An Hospital, Capital Medical University, Beijing, 100069, China

    Guang-ming Li

  7. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China

    Jin-han He

  8. Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Sheng Wang

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Contributions

All authors contributed to the study conception and design. XTY and AJQ designed the research. XTY, NZ, YTM, XYL, JMJ and YX helped to perform experiments. YTS, BJ, GML, SW, and JMZ collected the clinical samples. JHH and FJG contributed to the discussions and assisted language revision. AJQ supervised the work, drafted and critically revised the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ai-juan Qu.

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Yu, Xt., Zhao, N., Ma, Yt. et al. Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells. Acta Pharmacol Sin 47, 103–118 (2026). https://doi.org/10.1038/s41401-025-01628-1

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