PCSK9 mediates the oxidative low-density lipoprotein-induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway

Abstract

The present study aimed to explore the role and mechanisms of proprotein convertase subtilisin/kexin type 9 (PcSK9) in the oxidized low-density lipoprotein (oxLdL)-induced pyroptosis of vascular endothelial cells. For this purpose, human umbilical vein endothelial cells (HUVEcs) were incubated with oxLdL (100 µg/ml) for 24 h to induce pyroptosis, which was detected using PI/hoechst33342 double staining. The expression of pyroptosis-associated mole- cules was measured by western blot analysis and RT-qPcR. Reactive oxygen species (ROS) and membrane potential were examined through ROS probe and Jc-1 staining, respectively. PcSK9 and mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQcRc1) protein were knocked down by small interfering RNA (siRNA). PcSK9 was overexpressed by lentivirus. The results revealed that oxLdL induced HUVEc injury, pyroptosis and inflammatory factor release, and upregu- lated the expression of PcSK9 protein in the HUVEcs in a concentration-dependent manner. The silencing of PcSK9 expression with siRNA suppressed the oxLdL-induced damage to HUVEcs, the release of inflammatory substances and the occurrence of pyroptosis. In addition, oxLdL inhibited UQcRc1expression,promotedmitochondrialmembranepoten- tial collapse and damaged mitochondrial function; however, these processes were reversed by the silencing of PcSK9. PcSK9 overexpression induced the pyroptosis of HUVEcs, the generation of ROS and the disorder of mitochondrial func- tion by inhibiting UQcRc1. Therefore, PcSK9 mediates the oxLdL-induced pyroptosis of vascular endothelial cells via the UQcRc1/ROS pathway.