Docherty, C., Bresciani, J., Carswell, A., Chanderseka, A., Friel, E., Stasi, M. and Mercer, J. (2021) An inducible and vascular smooth muscle cell specific Pink-1 knockout induces mitochondrial dysfunction during atherogenesis. International Journal of Molecular Sciences, 22(18), 9993. (doi: 10.3390/ijms22189993) (PMID:34576157) (PMCID:PMC8467198)
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Abstract
DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its effect on VSMC-dependent atherogenesis in vivo and VSMC energetic metabolism in vitro. A smooth muscle cell-specific and MHC-Cre-inducible flox’d Pink1f/f kinase knockout was made on a ROSA26+/0 and ApoE−/− C57Blk6/J background. Mice were high fat fed for 10 weeks and vasculature assessed for physiological and pathogical changes. Mitochondrial respiratory activity was then assessed in wild-type and knockout animals vessels and isolated cells for their reliance on oxidative and glycolytic metabolism. During atherogenesis, we find that Pink1 knockout affects development of plaque quality rather than plaque quantity by decreasing VSMC and extracellular matrix components, collagen and elastin. Pink1 protein is important in the wild-type VSMC response to metabolic stress and induced a compensatory increase in hexokinase II, which catalyses the first irreversible step in glycolysis. Pink1 appears to play an important role in VSMC energetics during atherogenesis but may also provide insight into the understanding of mitochondrial energetics in other diseases where the regulation of energetic switching between oxidative and glycolytic metabolism is found to be important.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Carswell, Mr Andrew and Docherty, Dr Craig and Mercer, Dr John and Bresciani, Mr Jordan and Friel, Mrs Elaine |
| Authors: | Docherty, C., Bresciani, J., Carswell, A., Chanderseka, A., Friel, E., Stasi, M., and Mercer, J. |
| 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 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in International Journal of Molecular Sciences 22(18):9993 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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