Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway

Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis. Atherosclerosis is a condition where fats build up in arteries, causing heart disease. A study investigates the effect of Metformin, a diabetes drug, on this condition. Researchers studied how Metformin affects the aging of vascular smooth muscle cells. The study used cell cultures and mice to examine Metformin’s effect on cell aging and atherosclerosis. The experiment involved treating cells and mice with Metformin and observing changes in inflammation, plaque formation, and cell aging. The findings showed that Metformin slows down aging in VSMCs and reduces plaque formation in mice, indicating it might be useful beyond diabetes treatment. The study concludes that Metformin’s ability to enhance cell health and lessen atherosclerosis could be due to its impact on cell aging processes. This finding paves the way for using Metformin to prevent heart disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.