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      Hypoxia induces pulmonary arterial fibroblast proliferation, migration, differentiation and vascular remodeling via the PI3K/Akt/p70S6K signaling pathway

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          Abstract

          The present study was designed to examine whether hypoxia induces the proliferation, migration and differentiation of pulmonary arterial fibroblasts (PAFs) via the PI3K/Akt/p70S6K signaling pathway. PAFs were subjected to normoxia (21% O 2) or hypoxia (1% O 2). The proliferation, migration, differentiation and cellular p110α, p-Akt, and p-p70S6K expression levels of the PAFs were examined in vitro. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and right ventricular weight/body weight ratio (RV/BW) were examined. The expression levels of p110α, p-Akt, p70S6K, fibronectin and α-SMA in the rat pulmonary vessels were also examined. Hypoxia significantly elevated the proliferation, migration and differentiation of rat PAFs. It also strongly elevated the expression of p110α, p-Akt and p-p70S6K in PAFs in vitro. NVP-BEZ235 was revealed to significantly reduce the hypoxia-induced proliferation, migration and differentiation. In vivo experiments demonstrated that hypoxia significantly induced the elevation of RVSP, RVHI, RV/BW, medial thickening, adventitious thickening, and fibronectin and collagen deposition around pulmonary artery walls. The expression of p110α, p-Akt and p70S6K was evident in the pulmonary arteries of the hypoxic rats. NVP-BEZ235 significantly reduced the hypoxia-induced hypoxic pulmonary vascular remodeling, as well as fibronectin and collagen deposition in the pulmonary arteries. Therefore, hypoxia was demonstrated to induce the proliferation, migration and differentiation of PAFs and the hypoxic pulmonary vascular remodeling of rats via the PI3K/Akt/p70S6K signaling pathway.

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          Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.

          Sauveur-Michel Maira, Frédéric Stauffer, Josef Brueggen … (2008)
          The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
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            Inhibition of PI3K Prevents the Proliferation and Differentiation of Human Lung Fibroblasts into Myofibroblasts: The Role of Class I P110 Isoforms

            Enrico Conte, Mary Fruciano, Evelina Fagone … (2011)
            Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-β (TGF-β)-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-β signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the PI3K/Akt pathway in two critical stages of the fibrotic process induced by TGF-β: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of PI3Ks LY294002 is able to abrogate the TGF-β-induced increase in cell proliferation, in α- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the PI3K/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that PI3K p110δ and p110γ are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110α and β. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110γ and p110α in both TGF-β-induced fibroblast proliferation and differentiation. This finding suggests that specific PI3K isoforms can be pharmacological targets in IPF.
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              Role of the adventitia in pulmonary vascular remodeling.

              Kurt Stenmark, Evgenia Gerasimovskaya, Mita Das … (2006)
              An increasing volume of experimental data indicates that the adventitial fibroblast, in both the pulmonary and systemic circulations, is a critical regulator of vascular wall function in health and disease. A rapidly emerging concept is that the vascular adventitia acts as biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. In response to stress or injury, resident adventitial cells can be activated and reprogrammed to exhibit different functional and structural behaviors. In fact, under certain conditions, the adventitial compartment may be considered the principal injury-sensing tissue of the vessel wall. In response to vascular stresses such as overdistension and hypoxia, the adventitial fibroblast is activated and undergoes phenotypic changes, which include proliferation, differentiation, upregulation of contractile and extracellular matrix proteins, and release of factors that directly affect medial smooth muscle cell tone and growth and that stimulate recruitment of inflammatory and progenitor cells to the vessel wall. Each of these changes in fibroblast phenotype modulates either directly or indirectly changes in overall vascular function and structure. The purpose of this review is to present the current evidence demonstrating that the adventitial fibroblast acts as a key regulator of pulmonary vascular function and structure from the "outside-in."
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Med
                Journal ID (iso-abbrev): Int. J. Mol. Med
                Journal ID (publisher-id): IJMM
                Title: International Journal of Molecular Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1107-3756
                ISSN (Electronic): 1791-244X
                Publication date (Print): May 2018
                Publication date (Electronic): 06 February 2018
                Publication date PMC-release: 06 February 2018
                Volume: 41
                Issue: 5
                Pages: 2461-2472
                Affiliations
                [1 ]Department of Geriatrics, Peking University First Hospital, Beijing 100034
                [2 ]First Clinical Medical College of Peking University Health Science Center, Beijing 100083, P.R. China
                Author notes
                Correspondence to: Dr Xinmin Liu, Department of Geriatrics, Peking University First Hospital, 8 Xishiku Street, Beijing 100034, P.R. China, E-mail: lxm2128@ 123456163.com
                Article
                Publisher ID: ijmm-41-05-2461
                DOI: 10.3892/ijmm.2018.3462
                PMC ID: 5846667
                PubMed ID: 29436587
                SO-VID: c25cb5a9-49a3-48a4-9e91-8fb31f4dc67d
                Copyright © Copyright: © Chai et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 18 March 2017
                Date accepted : 29 November 2017
                Categories
                Subject: Articles

                Keywords: hypoxia,phosphatidylinositol-3-kinase,pulmonary arterial fibroblasts,proliferation,vascular remodeling
                Data availability:
                Keywords: hypoxia, phosphatidylinositol-3-kinase, pulmonary arterial fibroblasts, proliferation, vascular remodeling

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