SIRT1/PGC-1α/Mfn2 pathway regulates mitochondrial homeostasis in VSMC to attenuate aging-related vascular calcification

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Aging-related vascular calcification is closely associated with the development and progression of arterial diseases in elderly patients. Studies have shown that mitochondrial fusion/fission imbalance plays a crucial role in the formation of aging-related vascular calcification, and upregulation of silent information regulator 1 (SIRT1) blocks mitochondrial damage thereby protecting vascular smooth muscle cells (VSMCs). Our study aimed to explore whether SIRT1 can inhibit the vascular calcification and its potential molecular mechanism. VSMCs were used to establish the vascular aging model, and confirmed by β-galactosidase staining. The overexpressed SIRT1 and si-PGC-1α were transfected into VSMCs and verified by RT-qPCR or Western Blot. Proteins relevant to vascular calcification were detected by ELISA, while the level of calcified nodules was stained by Alizarin Red S. The molecules relevant to mitochondrial fusion were detected by RT-qPCR and immunofluorescence. Mito Tracker staining was used to evaluate the mitochondrial membrane potential and morphology. The level of ROS and ATP in VSMCs and its supernatant were detected by reagent kits combined flow cytometry. The levels of β-galactosidase and calcification were higher in the senescent VSMCs compared to normal VSMCs, while mitochondrial membrane potential and fusion and the expression of the SIRT1/PGC-1α/Mfn2 pathway were reduced. Overexpression of SIRT1 promoted its downstream targets PGC-1α and Mfn2 expression and reversed these aging characteristics, inhibited VSMC apoptosis and ROS level while increasing the ATP secretion compared to senescence VSMCs. Knocking down PGC-1α inhibit the function of SIRT1 overexpression on senescence VSMCs. This study presents a novel mechanism to the mitochondria-mediated age-related vascular calcification, and provides the potential molecular targets for the prevention and treatment of arterial diseases in elderly patients.

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