The long coiled-coil protein NECC2 regulates oxLDL-induced endothelial oxidative damage and exacerbates atherosclerosis development in apolipoprotein E −/− mice

• Published in: Free radical biology & medicine Vol. 216; pp. 106 - 117
• Main Authors: Mu, Xin, Liu, Shu-Jun, Zheng, Lei-Yin, Ouyang, Chenxi, Abdalla, Ahmed M.E., Wang, Xin-Xin, Chen, Kai, Yang, Fei-Fei, Meng, Ning
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2024
• Subjects: Animals; Apolipoproteins - adverse effects; Apolipoproteins - metabolism; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis; Atherosclerosis - metabolism; Endothelium - metabolism; Lipoproteins, LDL - metabolism; Long coiled-coil proteins; Mice; Oxidative Stress; Oxidized low-density lipoprotein; Vascular endothelial cell; Vascular endothelial cell; Oxidized low-density lipoprotein; Long coiled-coil proteins; Atherosclerosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.03.001

Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE−/− mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis. [Display omitted] •Endothelial NECC2 promotes the development of atherosclerosis.•NECC2 contributes to oxLDL-induced endothelial oxidative damage.•NECC2-induced Cav-1 phosphorylation via Tyk2 promotes oxLDL accumulation in VECs.•Compound YF-307 inhibits endothelial oxidative damage and atherosclerosis.