3691

ITGB4

integrin, beta 4;ITGB4;integrin, beta 4

CD104 antigen|GP150|integrin beta-4|integrin beta-4 subunit

17q25

protein-coding

To understand whether integrin beta4 is involved in vascular endothelial cell (VEC) senescence, we examined integrin beta4 level changes, as well as P53 and reactive oxygen species (ROS) levels and alterations of phosphatidylcholine-specific phospholipase C (PC-PLC) activity before and after knocking-down integrin beta4 by small interfering RNA. We found integrin beta4, P53 and ROS levels increased significantly, while Ca(2+)-independent PC-PLC activity obviously decreased during VEC senescence. On the other hand, integrin beta4 down-regulation attenuated the senescence phenotype and reversed Ca(2+)-independent PC-PLC activity, and P53 and ROS levels. The data suggested that integrin beta4 might mediate VEC senescence through depressing Ca(2+)-independent PC-PLC and elevating the levels of P53 and ROS.

Increasing evidence has demonstrated that the senescence of vascular endothelial cells (VECs) has critical roles in the pathogenesis of vascular dysfunction. Finding important factors that regulate VEC senescence will help provide novel therapeutic strategies for vascular disorders. Previously, we found that integrin beta4 was involved in VEC senescence. However, the mechanism underlying VEC senescence mediated by integrin beta4 remains poorly understand. In this study, we used a mouse in vivo model and showed that the level of integrin beta4 in the endothelium of mouse thoracic aorta was increased during natural aging and atherosclerosis. Furthermore, we found that H-ras, caveolin-1, and AP-1 were implicated in the senescent signal pathway mediated by integrin beta4 in human umbilical vein ECs (HUVECs). Knockdown of integrin beta4 could attenuate HUVEC senescent features, including increased interleukin-8 (IL-8) release and decreased endothelial nitric oxide synthase (eNOS) and NO levels and mitochondrial membrane potential in vitro. Our findings provide new clues illustrating the mechanism of VEC senescence. Integrin beta4 might be a potential target for therapy in cardiovascular diseases.