2. Academic Validation
  3. Klotho ameliorates angiotension-II-induced endothelial senescence via restoration of autophagy by inhibiting Wnt3a/GSK-3β/mTOR signaling: A potential mechanism involved in prognostic performance of Klotho in coronary atherosclerotic disease

Klotho ameliorates angiotension-II-induced endothelial senescence via restoration of autophagy by inhibiting Wnt3a/GSK-3β/mTOR signaling: A potential mechanism involved in prognostic performance of Klotho in coronary atherosclerotic disease

  • Mech Ageing Dev. 2023 Feb 9;211:111789. doi: 10.1016/j.mad.2023.111789.
Qi Mao 1,  Mengyang Deng 2,  Jianhua Zhao 3,  Denglu Zhou 4,  Wuyang Tong 5,  Shangcheng Xu 6,  Xiaohui Zhao 7
Affiliations

Affiliations

  • 1 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: holygeneral1214@163.com.
  • 2 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: 403010408@qq.com.
  • 3 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: zhaojianhua0685@163.com.
  • 4 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: doctorzhou1990@163.com.
  • 5 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: 744707543@qq.com.
  • 6 Center of Laboratory Medicine, Chongqing Prevention and Treatment Center for Occupational Diseases, Chongqing 400060, China; Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, Chongqing 400060, China. Electronic address: xushangchengmito@163.com.
  • 7 Department of Cardiology, Institute of Cardiovascular Research, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: doctorzhaoxiaohui@yahoo.com.
PMID: 36764463 DOI: 10.1016/j.mad.2023.111789
Abstract

Objective: We aimed to evaluate the prognostic performance of circulating Klotho in coronary atherosclerotic disease (CAD), and to further explore the effect of Klotho on stress-mediated endothelial senescence and underlying mechanism.

Methods: A cohort of 295 patients had a 12-month follow-up for major adverse cardiovascular events (MACE). Serum Klotho was detected by Enzyme linked immunosorbent assay. Cell viability, SA-β-Gal staining, the expression of P53 and P16 were analyzed for endothelial senescence. Oxidative stress was evaluated by measurement of Reactive Oxygen Species, superoxide dismutase and malondialdehyde. LC3, p62, Wnt3a, GSK-3β and mTOR were analyzed by western blotting. Autophagosome formation was detected by adenovirus transfection.

Results: In epidemiological analysis, low Klotho (≤295.9 pg/ml) was significantly associated with MACE risk (HR=2.266, 95 %CI 1.229-4.176). In experimental analysis, Klotho alleviated endothelial senescence and oxidative stress caused by Ang-II exposure; Klotho restored impaired autophagic flux to ameliorate Ang-II induced endothelial senescence; Ang-II activated Wnt3a/GSK-3β/mTOR signaling to inhibit Autophagy, whereas Klotho restored Autophagy through blockade of Wnt3a/GSK-3β/mTOR signaling; Klotho ameliorated endothelial senescence by suppressing Wnt3a/GSK-3β/mTOR pathway under Ang-II exposure.

Conclusions: Prognostic significance of Klotho in CAD is potentially ascribed to its anti-endothelial senescence effect via autophagic flux restoration by inhibiting Wnt3a/ GSK-3β/mTOR signaling.

Keywords

Autophagy; Coronary atherosclerotic disease; Endothelial senescence; Klotho; Wnt signaling.

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