二甲双胍
安普克
衰老
医学
炎症
线粒体
线粒体ROS
药理学
内科学
内分泌学
糖尿病
癌症研究
氧化应激
生物
细胞生物学
磷酸化
蛋白激酶A
作者
Sriravali Pulipaka,Gajalakshmi Singuru,Sashikanta Sahoo,Altab Shaikh,Rajamannar Thennati,Srigiridhar Kotamraju
出处
期刊:GeroScience
[Springer International Publishing]
日期:2023-11-16
卷期号:46 (2): 2391-2408
被引量:2
标识
DOI:10.1007/s11357-023-01015-w
摘要
Atherosclerosis, in general, is an age-associated cardiovascular disease wherein a progressive decline in mitochondrial function due to aging majorly contributes to the disease development. Mitochondria-derived ROS due to dysregulated endothelial cell function accentuates the progression of atherosclerotic plaque formation. To circumvent this, mitochondrially targeted antioxidants are emerging as potential candidates to combat metabolic abnormalities. Recently, we synthesized an alkyl TPP+ tagged esculetin (Mito-Esc), and in the current study, we investigated the therapeutic efficacies of Mito-Esc and metformin, a well-known anti-diabetic drug, in the amelioration of age-associated plaque formation in the aortas of 12 months aged Apoe−/− and 20 months aged C57BL/6 mice, in comparison to young C57BL/6 control mice. Administration of Mito-Esc or metformin significantly reduced age-induced atherosclerotic lesion area, macrophage polarization, vascular inflammation, and senescence. Further, chronic passaging of human aortic endothelial cells (HAEC) with either Mito-Esc or metformin significantly delayed cellular senescence via the activation of the AMPK-SIRT1/SIRT6 axis. Conversely, depletion of either AMPK/SIRT1/SIRT6 caused premature senescence. Consistent with this, Mito-Esc or metformin treatment attenuated NFkB-mediated inflammatory signaling and enhanced ARE-mediated anti-oxidant responses in comparison to late passage control HAECs. Importantly, culturing of HAECs for several passages with either Mito-Esc or metformin significantly improved mitochondrial function. Overall, Mito-Esc and metformin treatments delay age-associated atherosclerosis by regulating vascular senescence via the activation of AMPK-SIRT1/SIRT6 axis.
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