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

摘要

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 mu g/ml) for 24 h to induce pyroptosis, which was detected using PI/hoechst33342 double staining. The expression of pyroptosis-associated molecules 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 upregulated 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 UQCRC1 expression, promoted mitochondrial membrane potential 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 function by inhibiting UQCRC1. Therefore, PCSK9 mediates the oxLDL-induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway.