An Inducible and Vascular Smooth Muscle Cell-Specific Pink1 Knockout Induces Mitochondrial Energetic Dysfunction during Atherogenesis
| Autor: | John Mercer, Craig K. Docherty, Jordan Bresciani, Andrew Carswell, Amrita Chanderseka, Marianna Stasi, E Friel |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Vascular smooth muscle
DNA damage QH301-705.5 Myocytes Smooth Muscle oxidative phosphorylation PINK1 Oxidative phosphorylation Article Muscle Smooth Vascular Catalysis Inorganic Chemistry Mice mitochondrial dysfunction Animals Glycolysis Phosphorylation Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy Mice Knockout biology Chemistry Kinase Organic Chemistry General Medicine glycolysis Computer Science Applications Cell biology Oxidative Stress biology.protein atherosclerosis Microdissection Protein Kinases Elastin Homeostasis Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 9993, p 9993 (2021) International Journal of Molecular Sciences Volume 22 Issue 18 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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