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.
Highlights
The vascular smooth muscle cells (VSMCs) phenotype in the plaque is tightly coupled to the energetic state of the cell, with changes in VSMC plasticity directly related to changes in cellular metabolism [9]. This accelerated aging phenotype is found in explant human VSMCs in culture [10]; for example, we found that cells isolated from human carotid endarterectomy specimens show loss of mitochondrial integrity as flagged by Pink1 [8,11]
We find that human cells have an increased abundance in phosphorylation of the energy sensor Adenosine Triphosphate (ATP) sensor AMP Kinase (AMPK) at Thr172 and increased glycolytic protein expression in the plaque cap [8]
X-gal staining was confirmed across entire sections of aortic rings of vessels and is counterstained with eosin abdominal aortic tissue were stained blue in presence of X-gal when Pink was excised and Cre was activated. (G) A Pink1(lower pair). (F) Whole abdominal aortic tissue were stained blue in presence of X-gal when Pink was excised and Cre was KO VSMC line was derived from Pinkf/f explant whole aortae and treatedwith hydroxytamoxifen (OHT) in culture to f/f explant whole aortae and treatedwith hydroxytamoxifen activated
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. DNA damage and mitochondrial dysfunction are discerning characteristics of human atherosclerosis [1,2,3]. Regulation of mitochondrial integrity is controlled by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink). Human plaque vascular smooth muscle cells (pVSMCs) age faster than surrounding vessel wall cells and consequentially rely on a p53-dependent cell signalling program that drives cyclin-dependent kinase inhibitor (CDKi) activity that sensitises plaque cells to readily undergo apoptosis [4,5]
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