The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.
The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.
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CDK9-CYCLIN T1复合物通过诱导转录因子CHOP的表达来介导饱和脂肪酸诱导的血管钙化。
DOI：
10.1074/jbc.ra118.004706
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发表时间：
2018-11-02
期刊：
影响因子：
--
通讯作者：
Miyazaki M
中科院分区：
文献类型：
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作者：
Shiozaki Y;Okamura K;Kohno S;Keenan AL;Williams K;Zhao X;Chick WS;Miyazaki-Anzai S;Miyazaki M
血管钙化（或矿化）是慢性肾脏疾病（CKD）的常见并发症，与死亡率和发病率的增加密切相关。我们最近报道了通过饱和脂肪酸（SFA）诱导的内质网（ER）应激反应激活激活转录因子4 （ATF4）通路在ckd相关血管钙化中起致病作用。本研究利用小鼠CKD模型，我们1)研究了促凋亡转录因子CCAAT增强子结合蛋白同源蛋白（CHOP）对CKD依赖性内侧钙化的贡献，2)我们发现了内质网应激介导的CHOP表达的额外调节因子。具有平滑肌细胞（SMC）特异性CHOP表达的转基因小鼠在CKD下发生严重的血管凋亡和内侧钙化。蛋白激酶抑制剂文库的筛选鉴定出16种化合物，其中包括7种细胞周期蛋白依赖性激酶（CDK）抑制剂，可显著抑制内质网应激下CHOP的诱导。此外，选择性CDK9抑制剂和CRISPR/ cas9介导的CDK9还原可阻断sfa介导的CHOP表达诱导，而其他CDK亚型抑制剂则没有。敲除Cyclin T1抑制sfa介导的CHOP和矿化，而删除Cyclin T2和Cyclin K则促进CHOP的表达水平和矿化。值得注意的是，CDK9-cyclin T1复合体直接磷酸化并激活ATF4。这些结果表明，CDK9-cyclin T1和CDK9-cyclin T2/K复合物在CHOP表达和ckd诱导的血管钙化中具有相反的作用。他们进一步揭示了CDK9-cyclin T1复合物通过CHOP诱导和磷酸化介导的ATF4激活介导血管钙化。
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.