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Updated: May 23, 2025
Isolation of Primary Patient-specific Aortic Smooth Muscle Cells and Semiquantitative Real-time Contraction Measurements In Vitro
Published on: February 15, 2022
SIRT3 Represses Vascular Remodeling via Reducing Mitochondrial Ac-CoA Accumulation in Vascular Smooth Muscle Cells
Mei You1, Bowen Wang1, Li Li1
1Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, China (M.Y., B.W., L.L., M.L., L.W., T.C., Q.Z., A.M., H.W., M.S., Z.L., Z.Z., Z.Y., P.G.).
Background:
Vascular remodeling characterized by vascular smooth muscle cell (VSMC) phenotypic switching is a key pathological process leading to numerous cardiovascular diseases, often accompanied by a decrease in mitochondrial oxidative phosphorylation. However, whether VSMC mitochondrial homeostasis plays a central role in vascular remodeling remains elusive. In this study, we investigated the role of SIRT3 (sirtuin 3), a deacetylase that maintains mitochondrial homeostasis, in vascular remodeling.
Methods:
We established a VSMC-specific SIRT3 knockout mouse and a VSMC-specific SIRT3 overexpression mouse. Mice were infused with Ang II (angiotensin II) to establish the conventional abdominal aortic aneurysm model and underwent carotid artery ligation to establish the neointima formation model to investigate the role of SIRT3 in vascular remodeling. In vitro, quiescent-state VSMCs were stimulated with PDGF-BB (platelet-derived growth factor type BB) to investigate the direct role of SIRT3 in VSMC phenotypic switching, and the detailed mechanisms were investigated.
Results:
The expression and activity of SIRT3 were decreased in the aortas from mice with Ang II-induced abdominal aortic aneurysm or ligation-induced neointima formation. VSMC-specific knockout of SIRT3 exacerbated vascular remodeling, whereas overexpression or activation of SIRT3 in VSMCs displayed therapeutic effect. Moreover, the reduction of SIRT3 was shown to increase the expression level of KLF4 (Kruppel-like factor 4), an important transcription factor that orchestrates VSMC phenotypic switching. Mechanistically, SIRT3 repression caused mitochondrial Ac-CoA (acetyl coenzyme A) accumulation that increased acetylated histone 3 lysine 27 levels in the KLF4 gene promoter region. Blockage of mitochondrial Ac-CoA transporting into the cytoplasm by inhibiting ACLY (ATP-citrate lyase) also inhibited VSMC phenotypic switching and thus attenuated vascular remodeling even when SIRT3 was knocked down.
Conclusions:
This study provides evidence that mitochondrial dysfunction induced by SIRT3 inhibition is a major factor leading to VSMC phenotypic switching and vascular remodeling. Restoration of mitochondrial function and inhibition of mitochondrial Ac-CoA accumulation by activation of SIRT3 may help to treat remodeling-related cardiovascular damage.
