%0 Journal Article
%T SphK1/S1P mediates TGF
%A Cui Zhai
%A Fangwei Li
%A Jian Wang
%A Lu Liu
%A Manxiang Li
%A Qingting Wang
%A Shaojun Li
%A Wei Feng
%A Wenhua Shi
%A Xin Yan
%A Xinming Xie
%A Yanting Zhu
%J Pulmonary Circulation
%@ 2045-8940
%D 2019
%R 10.1177/2045894018816977
%X The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-¦Â1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-¦Â1-induced Notch3 activation in PASMC. In addition, we showed that TGF-¦Â1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-¦Â1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-¦Â1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension
%K SphK1/S1P
%K Smad2/3
%K Notch3
%K PASMC
%K proliferation
%U https://journals.sagepub.com/doi/full/10.1177/2045894018816977