최형철 (영남대학교)

한빛사논문

조회68

영남대학교

Exp. Mol. Med., Sep 02 2024, | https://doi.org/10.1038/s12276-024-01297-w Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway

Jin Young Sung^1,2, Seul Gi Kim^1,2, So-Young Park^2,3, Jae-Ryong Kim^2,4 and Hyoung Chul Choi^1,2

¹Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.

²Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.

³Department of Physiology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.

⁴Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.

Corresponding author

Correspondence to Hyoung Chul Choi.

Abstract

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.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-03)
연구진국내 연구진
분야 생명과학 > 분자생물학

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