scholarly journals Role for miR-204 in human pulmonary arterial hypertension

2011 ◽  
Vol 208 (3) ◽  
pp. 535-548 ◽  
Author(s):  
Audrey Courboulin ◽  
Roxane Paulin ◽  
Nellie J. Giguère ◽  
Nehmé Saksouk ◽  
Tanya Perreault ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Factor ◽  
Regulatory Pathway ◽  
Down Regulation ◽  
Activated T Cells ◽  
Proliferation And Apoptosis ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.

scholarly journals Upregulation of IRF9 Contributes to Pulmonary Artery Smooth Muscle Cell Proliferation During Pulmonary Arterial Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Yong-Jie Chen ◽  
Yi Li ◽  
Xian Guo ◽  
Bo Huo ◽  
Yue Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Signaling Pathway ◽  
Chronic Hypoxia ◽  
Pathological Feature ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a critical pathological feature in the pathogenesis of pulmonary arterial hypertension (PAH), but the regulatory mechanisms remain largely unknown. Herein, we demonstrated that interferon regulatory factor 9 (IRF9) accelerated PASMCs proliferation by regulating Prohibitin 1 (PHB1) expression and the AKT-GSK3β signaling pathway. Compared with control groups, the rats treated with chronic hypoxia (CH), monocrotaline (MCT) or sugen5416 combined with chronic hypoxia (SuHx), and mice challenged with CH had significantly thickened pulmonary arterioles and hyperproliferative PASMCs. More importantly, the protein level of IRF9 was found to be elevated in the thickened medial wall of the pulmonary arterioles in all of these PAH models. Notably, overexpression of IRF9 significantly promoted the proliferation of rat and human PASMCs, as evidenced by increased cell counts, EdU-positive cells and upregulated biomarkers of cell proliferation. In contrast, knockdown of IRF9 suppressed the proliferation of rat and human PASMCs. Mechanistically, IRF9 directly restrained PHB1 expression and interacted with AKT to inhibit the phosphorylation of AKT at thr308 site, which finally led to mitochondrial dysfunction and PASMC proliferation. Unsurprisingly, MK2206, a specific inhibitor of AKT, partially reversed the PASMC proliferation inhibited by IRF9 knockdown. Thus, our results suggested that elevation of IRF9 facilitates PASMC proliferation by regulating PHB1 expression and AKT signaling pathway to affect mitochondrial function during the development of PAH, which indicated that targeting IRF9 may serve as a novel strategy to delay the pathological progression of PAH.

scholarly journals The role of nuclear factor of activated T cells in pulmonary arterial hypertension

Cell Cycle ◽  
2017 ◽  
Vol 16 (6) ◽  
pp. 508-514 ◽  
Author(s):  
Rui Chen ◽  
Jinchuan Yan ◽  
Peijing Liu ◽  
Zhongqun Wang ◽  
Cuiping Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Pulmonary Arterial

scholarly journals Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A)

2021 ◽  
Vol 41 (3) ◽  
pp. 1205-1217 ◽  
Author(s):  
Ryo Kurosawa ◽  
Kimio Satoh ◽  
Takashi Nakata ◽  
Tomohiko Shindo ◽  
Nobuhiro Kikuchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Inflammatory Cytokines ◽  
Cyclophilin A ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Objective: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. Conclusions: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.

scholarly journals The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted

2007 ◽  
Vol 104 (27) ◽  
pp. 11418-11423 ◽  
Author(s):  
S. Bonnet ◽  
G. Rochefort ◽  
G. Sutendra ◽  
S. L. Archer ◽  
A. Haromy ◽  
...  
Keyword(s):  
T Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Pulmonary Arterial
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