Inhibition of FHL1 inhibits cigarette smoke extract-induced proliferation in pulmonary arterial smooth muscle cells

Li, Yuping; Pu, Guimei; Chen, Chengshui; Yang, Li

doi:10.3892/mmr.2015.3787

Cited by 10 publications

(9 citation statements)

References 46 publications

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“…Thus, FHL1 may have exerted similar effect in the current HPH neonatal rat model. Additionally, the present data was consistent with previous findings that high expression of FHL1 was correlated with PASMC proliferation induced by cigarette smoke extract ( 29 ).…”

Section: Discussionsupporting

confidence: 93%

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Yao

et al. 2017

Exp Ther Med

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Numerous studies have demonstrated that altered expression levels of four and a half LIM domains 1 (FHL1) and P21 are necessary for hypoxia-induced pulmonary vascular remodeling in both adult rats and human patients with idiopathic pulmonary arterial hypertension. However, whether FHL1 and P21 are present in the pulmonary artery and whether these proteins affect pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH) in neonatal rats remain unknown. The present study investigated the effects of altered FHL1 and P21 expression on pulmonary vascular remodeling in neonatal rats with HPH. A total of 32 newborn Sprague-Dawley rats were exposed to hypoxia or room air for 7 or 14 days (n=8/subgroup). Parameters including the percentage of medial wall thickness (WT%), the percentage of medial wall area (WA%), right ventricular (RV) mean pressure, RV hypertrophy index (RVHI) and RV systolic pressure (RVSP) were measured to evaluate the development of HPH. Additionally, the expressions of FHL1 and P21 in the pulmonary artery smooth muscle cells (PASMCs) were measured by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemical staining. WA%, WT%, RV mean pressure, RVHI and RVSP were significantly increased in the HPH model group when compared with the control group (P<0.01). The protein expression levels of FHL1 were significantly increased in the HPH group (P<0.05), while the mRNA and protein expression levels of P21 were significantly reduced (P<0.05). Pearson correlation analysis indicated that the protein expressions of FHL1 and P21 were correlated with WA% and WT% (all P<0.001), and that the protein expression of P21 was negatively correlated with that of FHL1 (P<0.01). The results indicated that the expressions of FHL1 and P21 were altered in the PASMCs of newborn rats with HPH. Furthermore, FHL1 and P21 may serve important roles in pulmonary vascular remodeling.

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Section: Discussionsupporting

confidence: 93%

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Yao

et al. 2017

Exp Ther Med

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“…When ASMCs were transfected with calreticulin siRNA, the expression of calreticulin was significantly diminished at the mRNA level (P<0.05) and also suppressed at the protein level, compared with that in control siRNA-transfected ASMCs stimulated with 10% CSE. A previous study reported that calreticulin transcriptionally regulates C/EBP-α through a cis-regulatory CNG-rich loop in the mRNA of C/EBP-α (19). In the present study, knockdown of calreticulin resulted in an upregulation of the mRNA (P<0.05) and protein levels of C/EBP-α, and an increase in C/EBP-α expression in the nucleus in human ASMCs stimulated with 10% CSE (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been suggested that inhibition of four and a half LIM domains protein 1 limited the CSE-induced proliferation of pulmonary arterial SMCs and may represent a potential therapeutic target for pulmonary hypertension (19). Furthermore, the results of the present study revealed that CSE promoted the proliferation of ASMCs via induction of calreticulin, which inhibits the expression of C/EBP-α.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke extract promotes proliferation of airway smooth muscle cells through suppressing C/EBP-α expression

Guan

Cai²,

et al. 2017

Experimental and Therapeutic Medicine

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Cigarette smoke has been considered a major contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD). In COPD patients, the airway smooth muscle layer has been observed to be markedly thickened and the proliferation of airway smooth muscle cells (ASMCs) was therefore used by the present study as a model to assess the impact of cigarette smoke extract (CSE). ASMCs were exposed to various concentrations of CSE and the proliferation of the cells was analyzed by an MTT assay. Furthermore, the expression levels of calreticulin and CCAAT/enhancer-binding protein alpha (C/EBP-α) in CSE-stimulated ASMCs were determined by polymerase chain reaction and western blot analyses. In addition, the effects of RNA interference (RNAi) to knockdown calreticulin and/or C/EBP-α on ASMC proliferation were studied. CSE was found to promote the proliferation of ASMCs, which was associated with increased expression of calreticulin and decreased expression of C/EBP-α. Knockdown of calreticulin resulted in the upregulation of C/EBP-α and inhibition of cell proliferation, while simultaneous knockdown of C/EBP-α promoted cell proliferation. The present study revealed that CSE promoted the proliferation of ASMCs, which was mediated by inhibition of C/EBP-α. These findings shed new light on airway remodeling in COPD and may provide novel approaches for therapies.

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“…FHL1 expression is also found significantly upregulated in pulmonary hypertension, particularly in the pulmonary vasculature 32. Furthermore, FHL1 has an important role in CSE-induced proliferation of pulmonary arterial smooth muscle cells and hypoxia-induced pulmonary hypertension 33,34. However, numerous studies implied that FHL1 may have a tumor suppressor activity and play significant roles in tumorigenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

<p>Overexpression Of hsa-miR-664a-3p Is Associated With Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Via Targeting FHL1</p>

Zhong

Chen

Liu

et al. 2019

COPD

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BackgroundChronic obstructive pulmonary disease (COPD) is recognized as a chronic lung disease with incomplete reversible airflow limitation, but its pathophysiology was still not clear. This study aimed at investigating regulatory roles of special miRNA–mRNA axis in COPD development.MethodsDifferentially expressed miRNAs and downstream mRNAs were screened from the Gene Expression Omnibus (GEO) dataset by using the LIMMA package in R software. Weighted Gene Co-expression Network Analysis (WGCNA) was used to construct a co-expression network for COPD. The correlation of dysregulated miRNA(s) and COPD was analyzed, and miRNAs with significant differences were validated in peripheral blood mononuclear cells (PBMCs) from COPD patients by real-time PCR. Regulatory roles of candidate miRNAs and targeted mRNAs were investigated in vitro study.ResultsThirteen modules of co-expressed miRNAs and mRNAs were constructed from a selected cohort with WGCNA. Turquoise module with 12 differentially expressed miRNAs and 120 mRNAs was significantly correlated with COPD. The expression of hsa-miR-664a-3p, an upregulated miRNA in the module, was increased both in lung tissue and PBMCs from COPD patients, whereas that targeted four and a half LIM domains 1 (FHL1) gene was decreased and positively correlated with forced expiratory volume in 1 sec (FEV1)/forced vital capacity (FVC%) (r = 0.59, p < 0.01). In vitro, luciferase activity assay revealed FHL1 as a target of hsa-miR-664a-3p and it could be directly downregulated by overexpression of hsa-miR-664a-3p. Furthermore, cigarette smoke extract could increase hsa-miR-664a-3p level and decrease FHL1 level in Beas-2B cells.ConclusionThe present study validated significant upregulation of hsa-miR-664a-3p in COPD patients, and its target gene FHL1 was downregulated and positively correlated with FEV1/FVC%; both hsa-miR-664a-3p and FHL1 could be regulated by cigarette smoke extract. Results of bioinformatic analyses and expanded validation suggest that the axis from hsa-miR-664a-3p to FHL1 might play a key role in cigarette smoke-induced COPD, and the exact mechanism should be confirmed in further studies.

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Inhibition of FHL1 inhibits cigarette smoke extract-induced proliferation in pulmonary arterial smooth muscle cells

Cited by 10 publications

References 46 publications

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Cigarette smoke extract promotes proliferation of airway smooth muscle cells through suppressing C/EBP-α expression

<p>Overexpression Of hsa-miR-664a-3p Is Associated With Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Via Targeting FHL1</p>

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