Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway

Ying-Ju Lai,Wei-Jan Chen,Hsao-Hsun Hsu,Jong-Hwei S Pang,Gwo-Jyh Chang,Shu-Hui Lin,Chung-Chi Huang

doi:10.1038/s41598-017-09707-y

Abstract

The depletion of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH). We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline-induced PAH. We observed decreased PTEN and pCREB in idiopathic PAH versus control tissue. We reduced PTEN using small interfering RNA in human control pulmonary arterial smooth muscle cells (PASMCs) and observed an increase in pAKT. Consistent with PTEN knockdown in PASMCs, prostaglandin E1 (PGE1) induced pCREB expression to stimulate PTEN protein expression and inhibited pAKT in a time- and dose-dependent manner. The enhanced proliferation and migration of PASMCs following PTEN knockdown were significantly inhibited by PGE1 treatment. The PGE1-induced elevation of PTEN expression in PTEN-depleted PASMCs was decreased by the application of a PKA inhibitor and a CBP-CREB interaction inhibitor. Supplementation with a novel emulsion composition comprising PGE1 in rats with monocrotaline-induced PAH prevented pulmonary arterial remodeling and improved hemodynamics via the induced expression of PTEN. We conclude that PGE1 recruits pCREB/PTEN to decrease the migration and proliferation of PASMCs associated with PAH. This finding elucidates a relevant underlying mechanism of the PGE1/CREB/PTEN signaling pathway to prevent progressive PAH.

Highlights

The depletion of cyclic adenosine monophosphate response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH)
This study provides evidence of the promotion of PTEN expression by prostaglandin E1 (PGE1) via activation of protein kinase A (PKA)/cAMP response element binding protein (CREB) cascades to inhibit pAKT level
When using PGE1 for therapeutic prevention in the MCT-induced PAH model, significant PTEN induction and pAKT reduction were observed at pulmonary arteries of MCT-induced PAH rats

Summary

Result

Expression of CREB and PTEN in human donor and IPAH Lungs. To determine PTEN and CREB levels in human idiopathic pulmonary arterial hypertension (IPAH) lung tissue, we performed immunoblotting. The PGE1-induced pCREB and PTEN expression levels were inhibited by H89 (PKA inhibitor) at 1, 5, and 10 μmol/L in a concentration-dependent manner and by the CREB inhibitor at 1 μmol/L compared with PTEN-defective PASMCs without PGE1 treatment (Fig. 5a,b). Treatment with PGE1 can induce PTEN expression to suppress the proliferation and migration of PTEN-depleted PASMCs, but this was reversed by H89 and CREBi, reflecting a crucial role of pCREB and PKA-dependent pathway in PGE1-induced effects. PTEN expression was strongly elicited and pAKT was decreased following lipid/PGE1 treatment at 5 mg/kg/d; pCREB was slightly elicited by PGE1, suggesting that pCREB was increased in the nuclei of PASMCs by PGE1 Taken together, these results demonstrate a reversal in PTEN suppression by PGE1 in the PAH animal model

Discussion

Findings

Methods