An inducible and vascular smooth muscle cell specific Pink-1 knockout induces mitochondrial dysfunction during atherogenesis

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 > Institute of Cardiovascular and Medical Sciences
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences