SIRT1-dependent PGC-1α deacetylation by SRT1720 rescues progression of atherosclerosis by enhancing mitochondrial function

线粒体 细胞生物学 氧化应激 衰老 氧化磷酸化 生物 血管平滑肌 化学 生物化学 内分泌学 平滑肌
作者
Jin Young Sung,Seul Gi Kim,Young Jin Kang,So‐Young Park,Hyoung Chul Choi
出处
期刊:Biochimica Et Biophysica Acta - Molecular And Cell Biology Of Lipids [Elsevier]
卷期号:1869 (3): 159453-159453 被引量:1
标识
DOI:10.1016/j.bbalip.2024.159453
摘要

Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis via lipid-mediated mitochondrial dysfunction and oxidative stress. However, the mechanisms of mitochondrial dysfunction and VSMC senescence in atherosclerosis have not been established. Here, we investigated the mechanisms whereby signaling pathways regulated by SRT1720 enhance or regulate mitochondrial functions in atherosclerotic VSMCs to suppress atherosclerosis. Initially, we examined the effect of SRT1720 on oleic acid (OA)-induced atherosclerosis. Atherosclerotic VSMCs exhibited elevated expressions of BODIPY and ADRP (adipose differentiation-related protein) and associated intracellular lipid droplet markers. In addition, the expression of collagen I was upregulated by OA, while the expressions of elastin and α-SMA were downregulated. mtDNA copy numbers, an ATP detection assay, transmission electron microscopy (TEM) imaging of mitochondria, mitochondria membrane potentials (assessed using JC-1 probe), and levels of mitochondrial oxidative phosphorylation (OXPHOS) were used to examine the effects of SRT1720 on OA-induced mitochondrial dysfunction. SRT1720 reduced mtDNA damage and accelerated mitochondria repair in VSMCs with OA-induced mitochondria dysfunction. In addition, mitochondrial reactive oxygen species (mtROS) levels were downregulated by SRT1720 in OA-treated VSMCs. Importantly, SRT1720 significantly increased SIRT1 and PGC-1α expression levels, but VSMCs senescence, inflammatory response, and atherosclerosis phenotypes were not recovered by treating cells with EX527 and SR-18292 before SRT1720. Mechanistically, the upregulations of SIRT1 and PGC-1α deacetylation by SRT1720 restored mitochondrial function, and consequently suppressed VSMC senescence and atherosclerosis-associated proteins and phenotypes. Collectively, this study indicates that SRT1720 can attenuate OA-induced atherosclerosis associated with VSMC senescence and mitochondrial dysfunction via SIRT1-mediated deacetylation of the PGC-1α pathway.
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