Over-expression of PKGIα inhibits hypoxia-induced proliferation, Akt activation, and phenotype modulation of human PASMCs: The role of phenotype modulation of PASMCs in pulmonary vascular remodeling

Yi, Bin; Ning, Jiao-nin; Wang, Guansong; Qian, Guisheng; Lü, Kun

doi:10.1016/j.gene.2011.11.010

Cited by 34 publications

(29 citation statements)

References 27 publications

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“…After the adventitia and endothelia were removed, the pulmonary artery was cut into small pieces and then cultured using the tissue-sticking method [15]. The purity and identity of the PASMCs was verified by typical morphological patterns and immunocytochemical staining using specific monoclonal antibodies raised against SM α-actin, as previously reported [16,17]. The PASMCs were used for experiments between passages 5 and 9.…”

Section: Methodsmentioning

confidence: 99%

MiR-206 Controls the Phenotypic Modulation of Pulmonary Arterial Smooth Muscle Cells Induced by Serum from Rats with Hepatopulmonary Syndrome by Regulating the Target Gene, Annexin A2

Chen

Ning

et al. 2014

Cell Physiol Biochem

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Background: Hepatopulmonary syndrome (HPS) is a serious complication of advanced liver disease that is characterised by intrapulmonary vascular dilatation (IPVD) and arterial hypoxemia. Pulmonary vascular remodelling (PVR) is an important pathological feature of HPS, but the potential mechanisms underlying PVR remain undefined. Recent findings have established the essential role of changes in Annexin A2 (ANXA2) in controlling the phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs) in PVR associated with HPS. However, the mechanism by which upstream signalling regulates ANXA2 is unclear. Methods: In the present study, computational analysis was used to predict which miRNA might target the 3´-untranslated region (3´-UTR) of the ANXA2 mRNA. Real-time PCR and western blotting were performed to study the level of correlation between ANXA2 and the differentiation marker with the predicted miRNAs in PASMCs stimulated with serum from normal rats or those with HPS. Functional analysis of the miRNA and a luciferase reporter assay were performed to demonstrate that the predicted miRNA suppressed ANXA2 expression by directly targeting the predicted 3´-UTR site of the ANXA2 mRNA. Results: Computational analysis predicted that miR-206 would target the 3´-UTR of ANXA2 mRNA. In HPS rat serum-stimulated PASMCs, the expression of miR-206 displayed an inverse correlation with ANXA2, while a positive correlation was observed with the phenotypic marker smooth muscle α-actin (SM α-actin). The miRNA functional analysis and luciferase reporter assay demonstrated that miR-206 effectively downregulated the expression of ANXA2 by binding to the 3´-UTR of the ANXA2 mRNA. Consistently, miR-206 effectively inhibited the HPS rat serum-induced phenotypic modulation and proliferation, while these effects were reversed in ANXA2-overexpressing PASMCs. Conclusion: This study demonstrates that miR-206 inhibits the HPS rat serum-induced phenotypic modulation and proliferation in PASMCs by down-regulating ANXA2 gene expression.

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Section: Methodsmentioning

confidence: 99%

MiR-206 Controls the Phenotypic Modulation of Pulmonary Arterial Smooth Muscle Cells Induced by Serum from Rats with Hepatopulmonary Syndrome by Regulating the Target Gene, Annexin A2

Chen

Ning

et al. 2014

Cell Physiol Biochem

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“…TLR4 is widely expressed in pulmonary macrophages, airway epithelial cells, airway smooth muscle cells and vascular endothelial cells. Previous studies of the authors reported that TLR4 receptor mediates PI3K/NF-κB signaling during airway remodeling in asthma, which is an important signal pathway to regulate the bronchial smooth muscle cells to synthesize and secrete inflammatory factor (5). Some reports have demonstrated an increased expression of TLR4 in lung tissue of COPD patients (6).…”

Section: Introductionmentioning

confidence: 99%

LPS enhances TLR4 expression and IFN-γ production via the TLR4/IRAK/NF-κB signaling pathway in rat pulmonary arterial smooth muscle cells

Wang

Han

et al. 2017

Molecular Medicine Reports

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The aim of the present study was to investigate the role of the Toll-like receptor (TLR)4 signaling pathway in cellular response to lipopolysaccharide (LPS) in rat pulmonary artery smooth muscle cells (PASMCs). Chronic obstructive pulmonary disease (COPD) rats were established with passive inhaling cigarette smoke plus injection of LPS. The TLR4 protein in lung tissues was determined with immunohistochemical staining and protein levels of the components of the TLR4 pathway in PASMCs were analyzed with western blotting. The production of interferon (IFN)-γ upon LPS stimulation in PASMCs was measured with ELISA. TLR4 expression in lung tissue from COPD rats was increased obviously compared with that in normal group. LPS enhances TLR4 expression in rat PASMCs and induced production of IFN-γ dramatically. LPS treatment resulted in increased phosphor-interleukin-1 receptor-associated kinase (IRAK), IκB and IκB kinase, as well as the total protein of nuclear factor (NF)-κB p65. TLR4 inhibitor TAK-242, IRAK1/4 inhibitor and NF-κB inhibitor Bay 117082 were capable of suppressing the effects of LPS. TLR4 signaling pathway is functional in PASMCs, and may be involved in the inflammatory response during the pathogenesis of COPD.

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“…Studies indicate that cells that are deficient in PKGI, such as baby hamster kidney fibroblast (BHK) cells, and highly passaged vascular SMC acquire an undifferentiated and proliferative phenotype, whereas those in which PKGI activity is stimulated or reconstituted, such as some low-passage vascular SMC stimulated with cGMP, 3T3 fibroblasts, BHK cells, and highly passaged vascular SMC in which PKGI is expressed from plasmids or adenoviruses, appear more differentiated and less proliferative. The relationship between PKGI expression and vascular SMC phenotype has been further demonstrated in studies in which the decrease in differentiation protein markers, such as smooth muscle myosin heavy chain, vimentin, and calponin in vascular SMC with diminished PKGI expression or activity, was reversed by overexpression of PKGI (93)(94)(95). These studies have stimulated intensive efforts to identify mechanisms through which PKGI regulates cell phenotype.…”

Section: Discussionmentioning

confidence: 91%

Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport

Kato

Zhang

Roberts

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kato S, Zhang R, Roberts, Jr. JD. Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport. Am J Physiol Lung Cell Mol Physiol 305: L130 -L140, 2013. First published May 17, 2013 doi:10.1152/ajplung.00391.2012.-Nitric oxide and cGMP modulate vascular smooth muscle cell (SMC) phenotype by regulating cell differentiation and proliferation. Recent studies suggest that cGMP-dependent protein kinase I (PKGI) cleavage and the nuclear translocation of a constitutively active kinase fragment, PKGI␥, are required for nuclear cGMP signaling in SMC. However, the mechanisms that control PKGI proteolysis are unknown. Inspection of the amino acid sequence of a PKGI cleavage site that yields PKGI␥ and a protease database revealed a putative minimum consensus sequence for proprotein convertases (PCs). Therefore we investigated the role of PCs in regulating PKGI proteolysis. We observed that overexpression of PCs, furin and PC5, but not PC7, which are all expressed in SMC, increase PKGI cleavage in a dose-dependent manner in human embryonic kidney (HEK) 293 cells. Moreover, furin-induced proteolysis of mutant PKGI, in which alanines were substituted into the putative PC consensus sequence, was decreased in these cells. In addition, overexpression of furin increased PKGI proteolysis in LoVo cells, which is an adenocarcinoma cell line expressing defective furin without PC activity. Also, expression of ␣1-PDX, an engineered serpin-like PC inhibitor, reduced PC activity and decreased PKGI proteolysis in HEK293 cells. Last, treatment of low-passage rat aortic SMC with membrane-permeable PC inhibitor peptides decreased cGMP-stimulated nuclear PKGI␥ translocation. These data indicate for the first time that PCs have a role in regulating PKGI proteolysis and the nuclear localization of its active cleavage product, which are important for cGMP-mediated SMC phenotype. guanosine 3=,5=-cyclic monophosphate-dependent protein kinase I; proprotein convertase; nitric oxide and guanosine 3=,5=-cyclic monophosphate signaling NITRIC OXIDE (NO) and cGMP play an important role in regulating vascular function and structure. In several disease models, decreased NO and cGMP signaling are associated with dedifferentiation and excessive proliferation of vascular smooth muscle cells (SMC) (9, 60), which can contribute to vasomotor instability and hypertension. In models of newborn lung disease, for example, pulmonary injury often causes decreased NO and cGMP signaling, pulmonary SMC hyperplasia, pulmonary hypertension, right heart failure, and reduced somatic growth. In such cases, selective pulmonary NO treatment has been observed to decrease abnormal pulmonary artery SMC proliferation (66, 67), improve alveolar development (4,8,45,52), and prevent pulmonary hypertension (66,67).NO and cGMP regulate vascular SMC phenotype primarily by stimulating cGMP-dependent protein kinase I (PKGI) (10, 15, 47, 95) through mechanisms that are incompletely understood. PKGI is expressed in vascular SMC as two isofo...

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Over-expression of PKGIα inhibits hypoxia-induced proliferation, Akt activation, and phenotype modulation of human PASMCs: The role of phenotype modulation of PASMCs in pulmonary vascular remodeling

Cited by 34 publications

References 27 publications

MiR-206 Controls the Phenotypic Modulation of Pulmonary Arterial Smooth Muscle Cells Induced by Serum from Rats with Hepatopulmonary Syndrome by Regulating the Target Gene, Annexin A2

MiR-206 Controls the Phenotypic Modulation of Pulmonary Arterial Smooth Muscle Cells Induced by Serum from Rats with Hepatopulmonary Syndrome by Regulating the Target Gene, Annexin A2

LPS enhances TLR4 expression and IFN-γ production via the TLR4/IRAK/NF-κB signaling pathway in rat pulmonary arterial smooth muscle cells

Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport

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