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CDK1 inhibition reduces osteogenesis in endothelial cells in vascular calcification
Yan Zhao, Yang Yang, Xiuju Wu, Li Zhang, Xinjiang Cai, Jaden Ji, Sydney Chen, Abigail Vera, Kristina I. Boström, Yucheng Yao
Yan Zhao, Yang Yang, Xiuju Wu, Li Zhang, Xinjiang Cai, Jaden Ji, Sydney Chen, Abigail Vera, Kristina I. Boström, Yucheng Yao
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Research Article Cell biology Vascular biology

CDK1 inhibition reduces osteogenesis in endothelial cells in vascular calcification

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Abstract

Vascular calcification is a severe complication of cardiovascular diseases. Previous studies demonstrated that endothelial lineage cells transitioned into osteoblast-like cells and contributed to vascular calcification. Here, we found that inhibition of cyclin-dependent kinase (CDK) prevented endothelial lineage cells from transitioning to osteoblast-like cells and reduced vascular calcification. We identified a robust induction of CDK1 in endothelial cells (ECs) in calcified arteries and showed that EC–specific gene deletion of CDK1 decreased the calcification. We found that limiting CDK1 induced E-twenty-six specific sequence variant 2 (ETV2), which was responsible for blocking endothelial lineage cells from undergoing osteoblast differentiation. We also found that inhibition of CDK1 reduced vascular calcification in a diabetic mouse model. Together, the results highlight the importance of CDK1 suppression and suggest CDK1 inhibition as a potential option for treating vascular calcification.

Authors

Yan Zhao, Yang Yang, Xiuju Wu, Li Zhang, Xinjiang Cai, Jaden Ji, Sydney Chen, Abigail Vera, Kristina I. Boström, Yucheng Yao

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Figure 6

Limiting CDK1 reduces aortic calcification in diabetic Ins2Akita/+ mice.

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Limiting CDK1 reduces aortic calcification in diabetic Ins2Akita/+ mice....
(A and B) Alizarin red staining (A) and total aortic calcium (B) of descending aortas of Ins2Akita/+ mice after AT7519 administration (n = 10). Scale bars: 100 μm. (C) Immunoblotting of ETV2, osterix, and FLK1 in CD31+CD45– aortic cells isolated from Ins2Akita/+ mice after AT7519 administration. Positive and negative controls are the same as in Figures 3 and 5. Each lane represents an independent experimental group. (D) Micro-CT imaging of descending aortas of VE-cadherincre/ERT2 Cdk1fl/fl Ins2Akita/+ mice and VE-cadherincre/ERT2 Cdk1fl/fl mice after tamoxifen administration (n = 5). Scale bars: 50 μm. (E) Total aortic calcium and expression of CDK1 and ETV2 in CD31+CD45– aortic cells isolated from VE-cadherincre/ERT2 Cdk1fl/fl Ins2Akita/+ mice and VE-cadherincre/ERT2 Cdk1fl/fl mice after tamoxifen administration (n = 6). Data in B and E were analyzed for statistical significance by 1-way ANOVA with Tukey’s multiple-comparison test. The bounds of the boxes are upper and lower quartiles with data points, the line in the box is median, and whiskers are maximal and minimal values. **P < 0.001; ***P < 0.0001.

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