USP14-mediated NLRC5 upregulation inhibits endothelial cell activation and inflammation in atherosclerosis

Atherosclerosis, a chronic inflammatory condition that leads to a variety of life-threatening cardiovascular diseases, is a worldwide public health concern. Endothelial cells (ECs), which line the inside of blood vessels, play an important role in atherogenic initiation. Endothelial activation and inflammation are indispensable for the early stage of atherosclerosis. Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme that regulates the stability and activity of target proteins, has been identified as a potential therapeutic target for many inflammatory diseases. However, the role of USP14 on ECs is undefined. In this study, we found that USP14 is downregulated in either atherosclerosis patient specimens or oxidized low-density lipoprotein (ox-LDL)-stimulated ECs as compared to the control group. Overexpression of USP14 in ECs restrains ox-LDL-stimulated nuclear transcription factor kappa B (NF-κB) activation and subsequent adhesion molecule production. USP14 inhibits endothelium proinflammatory activation by suppressing the degradation of the negative regulator of NF-κB signaling, nod-like receptor family caspase recruitment domain family domain containing 5 (NLRC5). Finally, our in vivo experiments confirmed that USP14 adenovirus injection in apolipoprotein E deficient (ApoE−/−) mice fed with a western diet reduced the atherosclerotic lesion size, inhibited macrophage accumulation in the intima, and restricted the progression of atherosclerosis. Our results reveal that USP14 may represent a new therapeutic target for atherosclerosis. •Ox-LDL triggers an inflammatory response and endothelial activation.•USP14 restricts monocytes adhesion in ox-LDL-stimulated endothelial cells.•USP14 inhibits endothelial activation by interaction with NLRC5.•Adenovirus-USP14 injection attenuates the atherosclerotic lesion in ApoE−/− mice.