scholarly journals An Inducible and Vascular Smooth Muscle Cell-Specific Pink1 Knockout Induces Mitochondrial Energetic Dysfunction during Atherogenesis

2021 ◽  
Vol 22 (18) ◽  
pp. 9993
Author(s):  
Craig K. Docherty ◽  
Jordan Bresciani ◽  
Andy Carswell ◽  
Amrita Chanderseka ◽  
Elaine Friel ◽  
...  

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.

1998 ◽  
Vol 82 (2) ◽  
pp. 147-156 ◽  
Author(s):  
Yoshikazu Yonemitsu ◽  
Yasufumi Kaneda ◽  
Shinji Tanaka ◽  
Yutaka Nakashima ◽  
Kimihiro Komori ◽  
...  

2006 ◽  
Vol 173 (3) ◽  
pp. 417-429 ◽  
Author(s):  
Rong Hou ◽  
Liming Liu ◽  
Syed Anees ◽  
Shungo Hiroyasu ◽  
Nicholas E.S. Sibinga

The significance of cadherin superfamily proteins in vascular smooth muscle cell (VSMC) biology is undefined. Here we describe recent studies of the Fat1 protocadherin. Fat1 expression in VSMCs increases significantly after arterial injury or growth factor stimulation. Fat1 knockdown decreases VSMC migration in vitro, but surprisingly, enhances cyclin D1 expression and proliferation. Despite limited similarity to classical cadherins, the Fat1 intracellular domain (Fat1IC) interacts with β-catenin, inhibiting both its nuclear localization and transcriptional activity. Fat1 undergoes cleavage and Fat1IC species localize to the nucleus; however, inhibition of the cyclin D1 promoter by truncated Fat1IC proteins corresponds to their presence outside the nucleus, which argues against repression of β-catenin–dependent transcription by nuclear Fat1IC. These findings extend recent observations about Fat1 and migration in other cell types, and demonstrate for the first time its anti-proliferative activity and interaction with β-catenin. Because it is induced after arterial injury, Fat1 may control VSMC functions central to vascular remodeling by facilitating migration and limiting proliferation.


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