The protective role of YAP1 on ER stress-induced cell death in vascular smooth muscle cells

    loading  Checking for direct PDF access through Ovid

Abstract

Apoptosis of vascular smooth muscle cells (VSMCs) has been implicated in the progression of atherosclerosis, especially in vascular remodelling and plaque rupture. Although it is known that Yes-associated protein 1 (YAP1) is a critical molecule that regulates cell proliferation, differentiation and apoptosis, the role of YAP1 in VSMCs apoptosis remains unknown. In this study, we investigated whether YAP1 modulates VSMC apoptosis induced by endoplasmic reticulum (ER) stress. In cultured VSMC, tunicamycin caused cell death accompanied by an increase in caspase-3 processing and C/EBP homologous protein (CHOP) expression. YAP1 protein expression was downregulated by tunicamycin and the phosphorylation of YAP1 at the Ser127 site was significantly increased by tunicamycin. Tunicamycin further decreased cell viability followed by an increase in caspase-3 processing in the absence of YAP1 when compared with treatment only with tunicamycin or siYAP1. On the other hand, overexpression of a constitutively active YAP1 (YAP1-5SA), which lacks five serine phosphorylation sites, significantly prevented the caspase-3 processing and restored the decrease in cell viability induced by tunicamycin. Overexpression of YAP1-5SA significantly inhibited tunicamycin-induced caspase-8 processing without affecting phosphorylation of p-38 and Akt. Furthermore, the overexpression of YAP1-5SA significantly restored the decrease in ANKRD1 expression induced by tunicamycin. The inhibition of tunicamycin-induced caspase-3 cleavage by YAP1-5SA was markedly attenuated in ANKRD1-knockdown cells. These results demonstrate that ER stress can alter intracellular YAP1 protein expression in VSMCs and that YAP1 is protective against VSMC apoptosis induced by ER stress through inhibiting caspase8/3 activation mediated in part by upregulation of ANKRD1.

Related Topics

    loading  Loading Related Articles