Ubiquitin‐specific protease 7 mediates platelet‐derived growth factor‐induced pulmonary arterial smooth muscle cells proliferation

Abstract

Pulmonary arterial hypertension is a devastating pulmonary vascular disease, in which the pathogenesis is complicated and unclear. Pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathological feature of pulmonary arterial hypertension. It has been shown that ubiquitin‐specific protease 7 (USP7) is involved in cancer cell proliferation via deubiquitinating and stabilizing E3 ubiquitin ligase mouse double minute 2 (MDM2). However, the effect of USP7 and MDM2 on platelet‐derived growth factor (PDGF)‐induced PASMCs proliferation is uncertain. This study aims to explore this issue. Our results indicated that PDGF up‐regulated USP7 protein expression and stimulated PASMCs proliferation; this was accompanied with the increase of MDM2, forkhead box O4 (FoxO4) reduction and elevation of CyclinD1. While prior transfection of USP7 siRNA blocked PDGF‐induced MDM2 up‐regulation, FoxO4 down‐regulation, increase of CyclinD1 and cell proliferation. Pre‐depletion of MDM2 by siRNA transfection reversed PDGF‐induced reduction of FoxO4, up‐regulation of CyclinD1 and PASMCs proliferation. Furthermore, pre‐treatment of cells with proteasome inhibitor MG‐132 also abolished PDGF‐induced FoxO4 reduction, CyclinD1 elevation and cell proliferation. Our study suggests that USP7 up‐regulates MDM2, which facilitates FoxO4 ubiquitinated degradation, and subsequently increases the expression of CyclinD1 to mediate PDGF‐induced PASMCs proliferation.

Keywords

• pulmonary arterial smooth muscle cells
• proliferation
• ubiquitin‐specific protease 7 (USP7)
• mouse double minute 2 (MDM2)
• forkhead box O4 (FoxO4)