2. Academic Validation
  3. α-Ketoglutarate attenuates hyperlipidemia-induced endothelial damage by activating the Erk-Nrf2 signaling pathway to inhibit oxidative stress and mitochondrial dysfunction

α-Ketoglutarate attenuates hyperlipidemia-induced endothelial damage by activating the Erk-Nrf2 signaling pathway to inhibit oxidative stress and mitochondrial dysfunction

  • Antioxid Redox Signal. 2023 May 8. doi: 10.1089/ars.2022.0215.
Danyu Cheng 1,  Xuyun Liu 2,  Yilin Gao 3,  Li Cui 4,  Min Wang 5,  Yezi Zheng 6,  Weiqiang Lv 7,  Lin Zhao 8,  Jiankang Liu 9 10
Affiliations

Affiliations

  • 1 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; danyucheng9643@163.com.
  • 2 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; liuxuyun2015@126.com.
  • 3 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; gaoyilin39@163.com.
  • 4 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, ShanXi, Xi'an, Xi'an, Shaanxi, China, 710049; cuilitjpu@163.com.
  • 5 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; wm201522@163.com.
  • 6 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; yezielegant@163.com.
  • 7 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; 824705609@qq.com.
  • 8 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, Shaanxi, China; zhaolin2015@mail.xjtu.edu.cn.
  • 9 Xi'an Jiaotong University, 12480, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology,, Xi'an, Shaanxi, China.
  • 10 University of Health and Rehabilitation Sciences, School of Health and Life Sciences, Qingdao, Shandong, China; j.liu@mail.xjtu.edu.cn.
PMID: 37154729 DOI: 10.1089/ars.2022.0215
Abstract

Aims: α-Ketoglutarate (AKG) is an intermediate of the tricarboxylic acid cycle and a key hub linking amino acid metabolism and glucose oxidation. Previous studies have shown that AKG improved cardiovascular diseases such as myocardial infarction and myocardial hypertrophy through antioxidant and lipid-lowering characteristics. However, its protective effect and mechanism on endothelial injury caused by hyperlipidemia have not been elucidated yet. In this study, we tested whether AKG possesses protective effects on hyperlipidemia-induced endothelial injury and studied the mechenism.

Results: AKG administration both in vivo, and in vitro significantly suppressed the hyperlipidemia-induced endothelial damage, regulated ET-1 and NO levels and reduced the inflammatory factor IL-6 and MMP-1 by inhibiting oxidative stress and mitochondrial dysfunction. The protective effects were achieved by the mechanism of activating the Nrf2 phase II system through the ERK signaling pathway. AKG Innovation: These results reveal the role of the AKG-ERK-Nrf2 signaling pathway in the prevention of hyperlipidemia-induced endothelial damage, and suggest that AKG, as an mitochondria-targeting nutrient, is a potential drug for the treatment of endothelial damage in hyperlipidemia.

Conclusion: AKG ameliorated the hyperlipidemia-induced endothelial damage and inflammatory response by inhibiting oxidative stress and mitochondrial dysfunction.

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