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J Biol Chem. 2018 Nov 2;293(44):17008-17020. doi: 10.1074/jbc.RA118.004706. Epub 2018 Sep 12.

The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.

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From the Division of Renal Diseases and Hypertension, Department of Medicine, and.
the Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado 80045.
From the Division of Renal Diseases and Hypertension, Department of Medicine, and


Vascular calcification (or mineralization) is a common complication of chronic kidney disease (CKD) and is closely associated with increased mortality and morbidity rates. We recently reported that activation of the activating transcription factor 4 (ATF4) pathway through the saturated fatty acid (SFA)-induced endoplasmic reticulum (ER) stress response plays a causative role in CKD-associated vascular calcification. Here, using mouse models of CKD, we 1) studied the contribution of the proapoptotic transcription factor CCAAT enhancer-binding protein homologous protein (CHOP) to CKD-dependent medial calcification, and 2) we identified an additional regulator of ER stress-mediated CHOP expression. Transgenic mice having smooth muscle cell (SMC)-specific CHOP expression developed severe vascular apoptosis and medial calcification under CKD. Screening of a protein kinase inhibitor library identified 16 compounds, including seven cyclin-dependent kinase (CDK) inhibitors, that significantly suppressed CHOP induction during ER stress. Moreover, selective CDK9 inhibitors and CRISPR/Cas9-mediated CDK9 reduction blocked SFA-mediated induction of CHOP expression, whereas inhibitors of other CDK isoforms did not. Cyclin T1 knockout inhibited SFA-mediated induction of CHOP and mineralization, whereas deletion of cyclin T2 and cyclin K promoted CHOP expression levels and mineralization. Of note, the CDK9-cyclin T1 complex directly phosphorylated and activated ATF4. These results demonstrate that the CDK9-cyclin T1 and CDK9-cyclin T2/K complexes have opposing roles in CHOP expression and CKD-induced vascular calcification. They further reveal that the CDK9-cyclin T1 complex mediates vascular calcification through CHOP induction and phosphorylation-mediated ATF4 activation.


CDK9; CHOP; ER stress; atherosclerosis; cardiovascular disease; cyclin-dependent kinase (CDK); endoplasmic reticulum stress (ER stress); fatty acid; kidney disease; renal dysfunction; saturated fatty acids; vascular biology; vascular calcification; vascular smooth muscle cells

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