Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Noskovičová, Nina; Petřek, Martin; Eickelberg, Oliver; Heinzelmann, Katharina

doi:10.1165/rcmb.2014-0294tr

Cited by 80 publications

(71 citation statements)

References 256 publications

(262 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PI3K/Akt and ERK1/2 are two main intracellular signaling pathways activated by PDGF in PASMC proliferation [18]. Therefore, we determined the involvement of these two pathway in PDGF regulation of SphK1/S1P.…”

Section: Pdgf Up-regulates Sphk1 and S1p Expression Via Activation Ofmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. Methods: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. Results: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. Conclusion: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

show abstract

Section: Pdgf Up-regulates Sphk1 and S1p Expression Via Activation Ofmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…These observations suggest a key role of PAI-1 in the migration of endothelial cells induced by various angiogenic factors. In addition, we assessed whether PAI-1 inhibition by SK-216 affected the phosphorylation of ERK1/2 and AKT, two major downstream signaling targets of VEGF (37), FGF (38), PDGF (39), and HGF (40). Our results showed that the phosphorylation of ERK1/2 and AKT in HUVECs induced by these angiogenic factors, except for HGF-induced phosphorylation of ERK1/2, was not inhibited by SK-216.…”

Section: Discussionmentioning

confidence: 91%

Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma

et al. 2016

View full text Add to dashboard Cite

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. Ó2016 AACR.

show abstract

“…Hence, rather than a specific cell type being responsible for FF, it is likely that specific pathways of myofibroblast differentiation and proliferation are essential pathogenic components for FF formation. PDGF has been widely implicated in fibrotic disorders through the regulation of myofibroblast differentiation and proliferation, and BLM mouse models demonstrated that PDGFR signaling can be a promising therapeutic target for preventing lung fibrosis development (12)(13)(14)(15)(29)(30)(31). In terms of clinical relevance of PDGFR signaling in IPF pathogenesis, one of the representative target receptors of nintedanib, a multiple tyrosine kinase inhibitor causing significant reduction in the decline of forced vital capacity for IPF patients, is PDGFR (32).…”

Section: Discussionmentioning

confidence: 99%

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Kobayashi

Araya

Minagawa

et al. 2016

The Journal of Immunology

109

117

View full text Add to dashboard Cite

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

show abstract

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Cited by 80 publications

References 256 publications

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Contact Info

Product

Resources

About