Modulation of vascular endothelial cell senescence by integrin β4.
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 β4 was involved in VEC senescence. However, the mechanism underlying VEC senescence mediated by integrin β4 remains poorly understand. In this study, we used a mouse in vivo model and showed that the level of integrin β4 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 β4 in human umbilical vein ECs (HUVECs). Knockdown of integrin β4 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 β4 might be a potential target for therapy in cardiovascular diseases.
Sun
ChunHui
C
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, China.
Liu
Xia
X
Qi
Lei
L
Xu
JiPing
J
Zhao
Jing
J
Zhang
Yun
Y
Zhang
ShangLi
S
Miao
JunYing
J
D000367:Age Factors; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D034622:RNA Interference; D018808:Transcription Factor AP-1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D001057:Apolipoproteins E; C495540:CAV1 protein, human; C508606:CXCL8 protein, human; D051242:Caveolin 1; D039503:Integrin alpha6; D039663:Integrin beta4; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D018631:ras Proteins