Activation of Notch3 promotes pulmonary arterial smooth muscle cells proliferation via Hes1/p27Kip1 signaling pathway

Yang Song,Yonghong Zhang,Haoxiang Jiang,Yanting Zhu,Lu Liu,Wei Feng,Lan Yang,Yibin Wang,Manxiang Li

doi:10.1016/j.fob.2015.08.007

Abstract

Activation of the Notch3 cascade is involved in the development of pulmonary arterial hypertension by stimulating the proliferation of vascular smooth muscle cells. However, the detailed molecular mechanisms underlying this effect are still unclear. The present study aims to address this issue. We demonstrated that over-expression of intracellular domain of the Notch3 receptor (NICD3) by adenovirus transfection dramatically induced proliferation of primary cultured pulmonary artery smooth muscle cells. This was accompanied with up-regulation of Hes1 protein and down-regulation of p27Kip1 protein. More importantly, we observed that prior silencing of Hes1 with siRNA blocked NICD3 over-expression-induced p27Kip1 reduction and cell proliferation. The present study suggests that Hes1 lies downstream of NICD3 and particularly mediates Notch3 signaling-induced proliferation of pulmonary arterial smooth muscle cells by down-regulation of p27Kip1 expression.

Highlights

Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by sustained elevation of pulmonary arterial resistance and pulmonary arterial pressure (PAP) leading to right heart failure and death [1,2]
We provide direct evidence that activation of Notch3 signaling by over-expression of NICD3 stimulates primary cultured pulmonary arterial smooth muscle cells (PASMCs) proliferation; this effect is coupled to NICD3 up-regulation of Hes1 expression and subsequent downregulation of p27Kip1
The present study suggests that targeting Notch3 cascade might be a novel strategy for the management of PAH

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by sustained elevation of pulmonary arterial resistance and pulmonary arterial pressure (PAP) leading to right heart failure and death [1,2]. Pulmonary arterial remodeling, occurring mostly in the distal pulmonary arteries, is a hallmark of all types of PAH [3]. Excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is critical in the pathogenesis of pulmonary artery remodeling [4]. During the transition of PASMCs from quiescent to proliferative types, multiple signaling cascades are activated and mediate the phenotype change [5,6]. It is important to clarify these pathways and exploring key targets to suppress PASMCs proliferation. Notch signaling is a highly conserved cascade and plays an important role in determining cell proliferation and apoptosis [7]

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