1. Novel role of PKR in palmitate-induced Sirt1 inactivation and endothelial cell senescence
- Author
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Hong Yuan, Alex F. Chen, Le Li, Zhen Zhang, Ruifang Chen, Shenghua Zhou, Chunle Wang, Yiping Leng, Zhouyangfan Peng, and Yapei Li
- Subjects
0301 basic medicine ,Senescence ,MAP Kinase Kinase 4 ,Physiology ,viruses ,Palmitates ,C jun nh2 terminal kinase ,environment and public health ,eIF-2 Kinase ,03 medical and health sciences ,Sirtuin 1 ,Physiology (medical) ,Human Umbilical Vein Endothelial Cells ,Humans ,Protein kinase A ,Cellular Senescence ,biology ,Chemistry ,G1 Phase Cell Cycle Checkpoints ,Protein kinase R ,Cell biology ,Endothelial stem cell ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,biology.protein ,Human umbilical vein endothelial cell ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine - Abstract
Endothelial cell senescence is regarded as a vital characteristic of cardiovascular diseases. Elevated palmitate (PA) is an independent risk factor of cardiovascular diseases, but its role in endothelial cell senescence is currently unknown. During the course of studying the prosenescent role of PA, we discovered a key role of dsRNA-dependent protein kinase [protein kinase R (PKR)] in endothelial senescence. Exposure of human umbilical vein endothelial cells (HUVECs) to PA-induced cell senescence is characterized by increased levels of senescence-associated β-galactose glucosidase activity, excessive production of reactive oxygen species production, impaired cellular proliferation, and G1 phase arrest. This phenomenon is associated with an increase of PKR autophosphorylation and decreased activity of sirtuin 1 (Sirt1), a pivotal antisenescent factor. PKR inactivation by PKR siRNA or its phosphorylation inhibitor 2-aminopurine significantly attenuated PA-induced HUVEC senescence by reversing Sirt1 activity and its downstream signaling. Moreover, to study the regulatory mechanism between PKR and Sirt1, we found that PKR promotes JNK activation to inhibit Sirt1 activity and that this effect could be reversed by the JNK inhibitor SP600125. These findings provide evidence that PKR mediates PA-induced HUVEC senescence by inhibiting Sirt1 signaling. Our study provides novel insights into the actions and mechanisms of PKR in endothelial senescence. NEW & NOTEWORTHY This study first provides a novel observation that dsRNA-dependent protein kinase (PKR) mediates palmitate-induced sirtuin 1 inactivation and subsequent human umbilical vein endothelial cell senescence. Most importantly, these new findings will provide a potential therapeutic strategy to improve free fatty acid-induced endothelial senescence by targeting PKR in cardiovascular diseases.
- Published
- 2018