Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. (Nature Medicine. 2014; 20: 1289-1300.)

報告日期: 2015/04/21
報告時間: 15:10/16:00
報告學生: 許玲維(以英文報告)
講評老師: 江美治
附件下載: 下載[1464-1425857602-1.pdf] 

Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension

Rajkumar Savai et al., Nature Medicine. 2014; 20: 1289-1300.

Date: 2015.04.21

Place: Room 602

Speaker: Ling-Wei Hsu

Commentator: Dr. Meei-Jyh Jiang

Pulmonary hypertension (PH) is a progressive disease caused by pulmonary vascular remodeling, leading to pulmonary vascular resistance, increased pressure loading on the right ventricle (RV) and finally right-heart failure. PH is associated with a poor prognosis, and the prevalence is estimated up to 100 million people worldwide with high mortality. Current the PH therapy is focused on pulmonary vasodilation for symptomatic relief. In PH classification, pulmonary arterial hypertension (PAH) is the main group. Thus, finding a new molecular target or signaling pathways to reverse maladaptive inward for the PAH therapy is urgently needed. Pulmonary vascular remodeling is mainly characterized by pulmonary endothelial cells and artery smooth muscle cells (PASMCs) inflammation, migration, hyperproliferation and anti-apoptosis for vascular obstruction. The authors hypothesized that targeting downstream effectors on those abnormalities such as forkhead box O (FoxO) transcription factors could provide a new strategy for PAH. The FoxO family regulates many cellular processes, including cell cycle regulation, cell survival and metabolism. In this study, the authors use three models for PAH: (1) human idiopathic PAH (IPAH), (2) monocrotaline (MCT)-induced PAH rat model, (3) PAH induced by hypoxia and vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416 (hypoxia+SU5416). In human and experimental lungs, FOXO1 and its target genes (CCNB1, CCND1, CDKN1B, BCL6, GADD45A, FASLG, CAT, and SOD2) were dysregulated in PAH vessels. Besides that, the authors isolated PASMCs from human IPAH and experimental models to determine the FoxO1 in different pro-hypertensive growth factors. It showed that FoxO1 decreased under the stimuli (PDGF-BB, IGF-1, TNF-α, and IL-6). In addition, the authors transduced a nonphosphorylatable, constitutively active mutant of FoxO1 (Ad-Foxo1) to PAH PASMCs, and it decreased cell proliferation and migration and increased apoptosis. More than in vitro studies, the authors generated arterial SMC-Foxo1 KO mice, and induced PAH by hypoxia and MCT. They used Ad-Foxo1, paclitaxel (anti-neoplastic agent) and paclitaxel inhalation (abraxane) to treat PAH SMC-Foxo1 KO mice, and isolated PASMCs from PAH SMC-Foxo1 KO mice. The results showed that paclitaxel upregulated FoxO1 and reversed the development of PAH. Thus, the study provides strong evidence that dysregulated FoxO1 in pulmonary arteries is important in the pathogenesis of PAH, and the reconstitution of FoxO1 provides a new therapeutic target to reverse the vascular remodeling of PAH.

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