Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression

Zheng, Yaguo; Ma, Hong; Hu, Enci; Huang, Zhiwei; Cheng, Xiaoling; Xiong, Chang-ming

doi:10.1097/fjc.0000000000000302

Cited by 16 publications

(12 citation statements)

References 38 publications

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“…). Pharmacological inhibition of FGF signaling attenuates monocrotaline‐induced PH and rescues bone morphogenetic protein receptor II ( BMPR‐II ) expression (Zheng et al, ). Receptor tyrosine kinase (RTK) inhibitors such as suramin, ponatinib, and imatinib also result in beneficial effects in experimental PH (Izikki et al, ; Kang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases

Agha

Seeger

Bellusci

2016

Developmental Dynamics

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Fibroblast growth factors (FGFs) constitute a large family of polypeptides that are involved in many biological processes, ranging from prenatal cell-fate specification and organogenesis to hormonal and metabolic regulation in postnatal life. During embryonic development, these growth factors are important mediators of the crosstalk among ectoderm-, mesoderm-, and endoderm-derived cells, and they instruct the spatial and temporal growth of organs and tissues such as the brain, bone, lung, gut, and others. The involvement of FGFs in postnatal lung homeostasis is a growing field, and there is emerging literature about their roles in lung pathophysiology. In this review, the involvement of FGF signaling in a wide array of lung diseases will be summarized. Developmental Dynamics 246:235-244,

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Section: Introductionmentioning

confidence: 99%

Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases

Agha

Seeger

Bellusci

2016

Developmental Dynamics

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“…Because increased PA pressures cause the pulmonary valve to close prematurely and decrease the PAT and PAT/ET ratio, our findings suggest that hyperoxia-induces a PH phenotype, and this phenotype is augmented by endothelial ERK2 deficiency in neonatal mice. Interventions used to rescue the PH phenotype in adult rodents decrease ERK1/2 activation [63][64][65][66], suggesting that activation of these kinases promotes the development of PH. Similarly, Young et al [67] demonstrated that inhibition of c-kit signaling mitigates hypoxia-induced PH in neonatal mice by downregulating activation of ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

Menon

Shrestha

Barrios

et al. 2020

IJMS

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Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a significant lung morbidity of infants, and disrupted lung angiogenesis is a hallmark of this disease. We observed that extracellular signal-regulated kinases (ERK) 1/2 support angiogenesis in vitro, and hyperoxia activates ERK1/2 in fetal human pulmonary microvascular endothelial cells (HPMECs) and in neonatal murine lungs; however, their role in experimental BPD and PH is unknown. Therefore, we hypothesized that Tie2 Cre-mediated deficiency of ERK2 in the endothelial cells of neonatal murine lungs would potentiate hyperoxia-induced BPD and PH. We initially determined the role of ERK2 in in vitro angiogenesis using fetal HPMECs. To disrupt endothelial ERK2 signaling in the lungs, we decreased ERK2 expression by breeding ERK2flox/flox mice with Tie-Cre mice. One-day-old endothelial ERK2-sufficient (eERK2+/+) or –deficient (eERK2+/−) mice were exposed to normoxia or hyperoxia (FiO2 70%) for 14 d. We then performed lung morphometry, gene and protein expression studies, and echocardiography to determine the extent of inflammation, oxidative stress, and development of lungs and PH. The knockdown of ERK2 in HPMECs decreased in vitro angiogenesis. Hyperoxia increased lung inflammation and oxidative stress, decreased lung angiogenesis and alveolarization, and induced PH in neonatal mice; however, these effects were augmented in the presence of Tie2-Cre mediated endothelial ERK2 deficiency. Therefore, we conclude that endothelial ERK2 signaling is necessary to mitigate hyperoxia-induced experimental BPD and PH in neonatal mice. Our results indicate that endothelial ERK2 is a potential therapeutic target for the management of BPD and PH in infants.

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“…We found that TGF-betaR1 and smad4 were possible downstream targets of miR-140-5p, reduction in miR-140-5p in PAH might stimulate TGF-beta1/Smad4 pathway by upregulating TGF-betaR1 and smad4. Previous studies have demonstrated that PDGF, TLR4, VEGFA, and FGF contribute to the pathogenesis of PAH via activating various signaling pathways, especially PI3K/Akt cascade [24][25][26][27][28]. CREB, an important transcription factor lying downstream of PI3K/Akt pathway, mediates the partial functions of PI3K/Akt [29].…”

Section: Discussionmentioning

confidence: 99%

Prediction of target genes for miR‐140‐5p in pulmonary arterial hypertension using bioinformatics methods

Shi

Wan

et al. 2017

FEBS Open Bio

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The expression of micro RNA (miR)‐140‐5p is known to be reduced in both pulmonary arterial hypertension ( PAH ) patients and monocrotaline‐induced PAH models in rat. Identification of target genes for miR‐140‐5p with bioinformatics analysis may reveal new pathways and connections in PAH . This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR‐140‐5p to provide theoretical evidences for further researches on role of miR‐140‐5p in PAH . Multiple downstream target genes and upstream transcription factors ( TF s) of miR‐140‐5p were predicted in the analysis. Gene ontology ( GO ) enrichment analysis indicated that downstream target genes of miR‐140‐5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome ( KEGG ) pathway analysis found that downstream target genes were mainly located in Notch, TGF ‐beta, PI 3K/Akt, and Hippo signaling pathway. According to TF –mi RNA – mRNA network, the important downstream target genes of miR‐140‐5p were PPI , TGF ‐betaR1, smad4, JAG 1, ADAM 10, FGF 9, PDGFRA , VEGFA , LAMC 1, TLR 4, and CREB . After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR‐140‐5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro .

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Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression

Abstract: These results suggest that PD173074 can alleviate monocrotaline-induced pulmonary arterial hypertension and it may be a useful option for PAH. Our data also suggest a role of FGF-2/bone morphogenetic protein signaling interaction in PAH.

Cited by 16 publications

References 38 publications

Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases

Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

Prediction of target genes for miR‐140‐5p in pulmonary arterial hypertension using bioinformatics methods

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