Inducing energetic switching using Klotho improves vascular smooth muscle cell phenotype

Docherty, C. K., Strembitska, A., Baker, C. P., Schmidt, F. F., Reay, K. and Mercer, J. R. (2022) Inducing energetic switching using Klotho improves vascular smooth muscle cell phenotype. International Journal of Molecular Sciences, 23(1), 217. (doi: 10.3390/ijms23010217) (PMID:35008643) (PMCID:PMC8745077)

[img] Text
261337.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Abstract

The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mercer, Dr John and Docherty, Dr Craig and Strembitska, Anastasiya
Authors: Docherty, C. K., Strembitska, A., Baker, C. P., Schmidt, F. F., Reay, K., and Mercer, J. R.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:International Journal of Molecular Sciences
Publisher:MDPI
ISSN:1661-6596
ISSN (Online):1422-0067
Published Online:25 December 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in International Journal of Molecular Sciences 23(1): 217
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record