Format

Send to

Choose Destination
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.

Author information

1
From the Division of Renal Diseases and Hypertension, Department of Medicine, and.
2
the Department of Cell and Developmental Biology, University of Colorado Denver, Aurora, Colorado 80045.
3
From the Division of Renal Diseases and Hypertension, Department of Medicine, and makoto.miyazaki@ucdenver.edu.

Abstract

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.

KEYWORDS:

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

PMID:
30209133
PMCID:
PMC6222109
DOI:
10.1074/jbc.RA118.004706
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center