Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension.

Abstract:

:Heritable pulmonary arterial hypertension (HPAH) is a serious lung vascular disease caused by heterozygous mutations in the bone morphogenetic protein (BMP) pathway genes, BMPR2 and SMAD9. One noncanonical function of BMP signaling regulates biogenesis of a subset of microRNAs. We have previously shown that this function is abrogated in patients with HPAH, making it a highly sensitive readout of BMP pathway integrity. Ataluren (PTC124) is an investigational drug that permits ribosomal readthrough of premature stop codons, resulting in a full-length protein. It exhibits oral bioavailability and limited toxicity in human trials. Here, we tested ataluren in lung- or blood-derived cells from patients with HPAH with nonsense mutations in BMPR2 (n = 6) or SMAD9 (n = 1). Ataluren significantly increased BMP-mediated microRNA processing in six of the seven cases. Moreover, rescue was achieved even for mutations exhibiting significant nonsense-mediated mRNA decay. Response to ataluren was dose dependent, and complete correction was achieved at therapeutic doses currently used in clinical trials for cystic fibrosis. BMP receptor (BMPR)-II protein levels were normalized and ligand-dependent phosphorylation of downstream target Smads was increased. Furthermore, the usually hyperproliferative phenotype of pulmonary artery endothelial and smooth muscle cells was reversed by ataluren. These results indicate that ataluren can effectively suppress a high proportion of BMPR2 and SMAD9 nonsense mutations and correct BMP signaling in vitro. Approximately 29% of all HPAH mutations are nonsense point mutations. In light of this, we propose ataluren as a potential new personalized therapy for this significant subgroup of patients with PAH.

authors

Drake KM,Dunmore BJ,McNelly LN,Morrell NW,Aldred MA

doi

10.1165/rcmb.2013-0100OC

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

403-9

issue

3

eissn

1044-1549

issn

1535-4989

journal_volume

49

pub_type

杂志文章
  • Human alveolar macrophages inhibit receptor-mediated increases in intracellular calcium concentration in lymphocytes.

    abstract::Prior studies have demonstrated that human alveolar macrophages (AM) are suppressive of lymphocyte function, through the mechanism of inhibition is unclear. In the current study, human AM inhibited receptor-mediated increases in intracellular calcium concentration ([Ca2+]i) in T cells, natural killer cells, and B cell...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/5.5.411

    authors: Yarbrough WC Jr,Wilkes DS,Weissler JC

    更新日期:1991-11-01 00:00:00

  • alpha5beta1-integrin expression is essential for tumor progression in experimental lung cancer.

    abstract::The matrix glycoprotein, fibronectin, stimulates the proliferation of non-small cell lung carcinoma in vitro through α5β1 integrin receptor-mediated signals. However, the true role of fibronectin and its receptor in lung carcinogenesis in vivo remains unclear. To test this, we generated mouse Lewis lung carcinoma cell...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2009-0375OC

    authors: Roman J,Ritzenthaler JD,Roser-Page S,Sun X,Han S

    更新日期:2010-12-01 00:00:00

  • Early changes in the calcitonin gene-related peptide (CGRP) content of pulmonary endocrine cells concomitant with vascular remodeling in the hypoxic rat.

    abstract::Morphologic changes are reported to occur in rat lung vasculature after 3 days of hypoxia. We have previously shown that immunoreactivity for the vasodilator calcitonin gene-related peptide (CGRP) is increased in pulmonary endocrine cells by 7 days of hypoxia. Because these cells may be among the earliest mediators of...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/9.5.467

    authors: Roncalli M,Springall DR,Maggioni M,Moradoghli-Haftvani A,Winter RJ,Zhao L,Coggi G,Polak JM

    更新日期:1993-11-01 00:00:00

  • Modulators of sphingolipid metabolism reduce lung inflammation.

    abstract::The investigation of novel targets for the treatment of cystic fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistent with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in mice and patients with...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2010-0457OC

    authors: Dechecchi MC,Nicolis E,Mazzi P,Cioffi F,Bezzerri V,Lampronti I,Huang S,Wiszniewski L,Gambari R,Scupoli MT,Berton G,Cabrini G

    更新日期:2011-10-01 00:00:00

  • Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages.

    abstract::Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen spec...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2007-0130OC

    authors: Facchinetti F,Amadei F,Geppetti P,Tarantini F,Di Serio C,Dragotto A,Gigli PM,Catinella S,Civelli M,Patacchini R

    更新日期:2007-11-01 00:00:00

  • Active mTOR in Lung Epithelium Promotes Epithelial-Mesenchymal Transition and Enhances Lung Fibrosis.

    abstract::The mTOR pathway is one of the key signal cascades in the pathogenesis of idiopathic pulmonary fibrosis. Previous studies have mainly focused on this pathway in the fibroblasts and/or myofibroblasts, but not in the epithelial cells. In this study, we sought to investigate the role of the mTOR pathway in lung epithelia...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2019-0255OC

    authors: Saito M,Mitani A,Ishimori T,Miyashita N,Isago H,Mikami Y,Noguchi S,Tarui M,Nagase T

    更新日期:2020-06-01 00:00:00

  • Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation.

    abstract::Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-α1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preex...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2016-0077OC

    authors: Bharat A,Chiu S,Zheng Z,Sun H,Yeldandi A,DeCamp MM,Perlman H,Budinger GR,Mohanakumar T

    更新日期:2016-10-01 00:00:00

  • Interleukin-1 family member 9 stimulates chemokine production and neutrophil influx in mouse lungs.

    abstract::Interleukin-1 (IL-1) is a proinflammatory cytokine that signals through the Type I IL-1 receptor (IL-1RI). Novel IL-1-like cytokines were recently identified. Their functions in lung disease remain unclear. Interleukin-1 family member-9 (IL-1F9) is one such IL-1-like cytokine, expressed in the lungs of humans and mice...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2009-0315OC

    authors: Ramadas RA,Ewart SL,Medoff BD,LeVine AM

    更新日期:2011-02-01 00:00:00

  • Hyperoxia alone causes changes in lung proteoglycans and hyaluronan in neonatal rat pups.

    abstract::Specific changes in composition and content of lung extracellular matrix (ECM) proteoglycans (PGs) and hyaluronan (HA) have been observed during the acute response to damage in several forms of injury including infant respiratory distress syndrome (IRDS). These ECM components are thought to modulate the healing respon...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.13.6.7576700

    authors: Juul SE,Krueger RC Jr,Scofield L,Hershenson MB,Schwartz NB

    更新日期:1995-12-01 00:00:00

  • Thy-1 signals through PPARγ to promote lipofibroblast differentiation in the developing lung.

    abstract::Thy-1 is a glycosylphosphytidylinositol-linked cell-surface glycoprotein present on a subset of lung fibroblasts, which plays an important role in postnatal alveolarization. In the present study, we define the role of Thy-1 in pulmonary lipofibroblast differentiation and in the regulation of lipid homeostasis via pero...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2011-0316OC

    authors: Varisco BM,Ambalavanan N,Whitsett JA,Hagood JS

    更新日期:2012-06-01 00:00:00

  • Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

    abstract::Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine ...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2014-0493OC

    authors: Anvari S,Vyhlidal CA,Dai H,Jones BL

    更新日期:2015-12-01 00:00:00

  • Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway.

    abstract::Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2012-0451OC

    authors: Meng Y,Yu CH,Li W,Li T,Luo W,Huang S,Wu PS,Cai SX,Li X

    更新日期:2014-04-01 00:00:00

  • Smoke extract impairs adenosine wound healing: implications of smoke-generated reactive oxygen species.

    abstract::Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease, where it balances between tissue repair and excessive airway remodeling. We previously demonstrated that the activation of the adenosine A2A receptor promotes epithelial wound closure. However, the mec...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2011-0273OC

    authors: Allen-Gipson DS,Zimmerman MC,Zhang H,Castellanos G,O'Malley JK,Alvarez-Ramirez H,Kharbanda K,Sisson JH,Wyatt TA

    更新日期:2013-05-01 00:00:00

  • Plasminogen activation induced pericellular fibronectin proteolysis promotes fibroblast apoptosis.

    abstract::Apoptosis of fibroblasts/myofibroblasts is a critical event in the resolution of tissue repair responses; however, mechanisms for the regulation of (myo)fibroblast apoptosis/survival remain unclear. In this study, we demonstrate counter-regulatory interactions between the plasminogen activation system and transforming...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2007-0174OC

    authors: Horowitz JC,Rogers DS,Simon RH,Sisson TH,Thannickal VJ

    更新日期:2008-01-01 00:00:00

  • 2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity.

    abstract::High mobility group box 1 (HMGB1) is an alarmin released from macrophages after infection or inflammation and is a biomarker of lung disease progression in patients with cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits the release of HMGB1 from murine macrophages triggered by neutrophil el...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2016-0069OC

    authors: Zheng S,Kummarapurugu AB,Afosah DK,Sankaranarayanan NV,Boothello RS,Desai UR,Kennedy T,Voynow JA

    更新日期:2017-01-01 00:00:00

  • Bone marrow-derived mesenchymal stem cells in repair of the injured lung.

    abstract::We sought to determine whether an intact bone marrow is essential to lung repair following bleomycin-induced lung injury in mice, and the mechanisms of any protective effects conferred by bone marrow-derived mesenchymal stem cell (BMDMSC) transfer. We found that myelosupression increased susceptibility to bleomycin in...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2004-0330OC

    authors: Rojas M,Xu J,Woods CR,Mora AL,Spears W,Roman J,Brigham KL

    更新日期:2005-08-01 00:00:00

  • Effect of CTP:phosphocholine cytidylyltransferase overexpression on the mouse lung surfactant system.

    abstract::CTP:phosphocholine cytidylyltransferase (CT) is the rate-limiting enzyme in the biosynthesis by type II pneumocytes of phosphatidylcholine (PC), the predominant phospholipid in lung surfactant. Augmentation of endogenous CT activity might therefore result in enhanced surfactant PC production. To test this hypothesis, ...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.26.6.4720

    authors: Li J,Marsh JJ,Spragg RG

    更新日期:2002-06-01 00:00:00

  • Transforming growth factor beta 1 downregulates the platelet-derived growth factor alpha-receptor subtype on human lung fibroblasts in vitro.

    abstract::Fibroblasts are the central target cell in pulmonary fibrotic diseases, and their proliferation is mediated largely by platelet-derived growth factor (PDGF) isoforms secreted by activated lung macrophages. Several other macrophage-derived cytokines that are increased during fibrogenesis, including interleukin-1 beta a...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.13.4.7546780

    authors: Bonner JC,Badgett A,Lindroos PM,Osornio-Vargas AR

    更新日期:1995-10-01 00:00:00

  • MicroRNAs in pulmonary arterial hypertension.

    abstract::Pulmonary arterial hypertension (PAH) is a devastating disease without effective treatment. Despite decades of research and the development of novel treatments, PAH remains a fatal disease, suggesting an urgent need for better understanding of the pathogenesis of PAH. Recent studies suggest that microRNAs (miRNAs) are...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章,评审

    doi:10.1165/rcmb.2014-0166TR

    authors: Zhou G,Chen T,Raj JU

    更新日期:2015-02-01 00:00:00

  • Monkey Clara cell 10 kDa protein (CC10): a characterization of the amino acid sequence with an evolutional comparison with humans, rabbits, rats, and mice.

    abstract::Monkey Clara cell 10 kDa protein (CC10) was purified from monkey lung lavage. This protein showed an apparent molecular weight of about 10 kDa and 5 kDa under non-reducing and reducing conditions, respectively, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. From the amino acid sequence dat...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.15.3.8810640

    authors: Hashimoto S,Nakagawa K,Sueishi K

    更新日期:1996-09-01 00:00:00

  • Human mononuclear phagocytes express the insulin-like growth factor-II/mannose-6-phosphate receptor.

    abstract::The insulin-like growth factor (IGF)-II/mannose-6-phosphate (M6P) receptor, which targets acid hydrolases to lysosomes, is a multifunctional protein with separate binding sites for IGF-II and M6P. The purpose of this study was to determine if alveolar macrophages (AM) and their precursor cells, blood monocytes, expres...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/4.6.555

    authors: Rom WN

    更新日期:1991-06-01 00:00:00

  • Pulmonary fibrosis: searching for model answers.

    abstract::Substantial challenges remain in our understanding of fibrotic lung diseases. Nowhere is this more true than in the elucidation and verification of the pathogenetic basis upon which they develop. Scientific progress, most recently in the field of experimental therapy, has relied closely on interpreting data derived fr...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章,评审

    doi:10.1165/rcmb.2005-0062TR

    authors: Chua F,Gauldie J,Laurent GJ

    更新日期:2005-07-01 00:00:00

  • Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway.

    abstract::Metformin has been used as first-line treatment in patients with type 2 diabetes, and is reported to reduce cancer risk and progression by activating the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Cisplatin remains the main drug for treating advanced non-small-cell lung cancer. However, drug r...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2012-0244OC

    authors: Lin CC,Yeh HH,Huang WL,Yan JJ,Lai WW,Su WP,Chen HH,Su WC

    更新日期:2013-08-01 00:00:00

  • Temporal-spatial analysis of the immune response in a murine model of ovalbumin-induced airways inflammation.

    abstract::The objective of this study was to define phenotypic changes of antigen-presenting cells (APCs) and T cells in a murine model of antigen-induced airways inflammation that involves intraperitoneal sensitization with ovalbumin (OVA)/adjuvant followed by antigen aerosolization. We investigated the APC and T-cell compartm...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.25.3.4482

    authors: Gajewska BU,Swirski FK,Alvarez D,Ritz SA,Goncharova S,Cundall M,Snider DP,Coyle AJ,Gutierrez-Ramos JC,Stämpfli MR,Jordana M

    更新日期:2001-09-01 00:00:00

  • Regulation of hydrogen peroxide generation in cultured endothelial cells.

    abstract::Endogenous hydrogen peroxide (H2O2) release from aortic endothelial cells was studied in the presence of antioxidant enzyme inhibitors, mitochondrial inhibitors, a microsomal cytochrome P-450 inhibitor, and after oxidative stress induced with H2O2 or menadione. Extracellular H2O2 generation was determined spectrofluor...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/6.2.175

    authors: Kinnula VL,Whorton AR,Chang LY,Crapo JD

    更新日期:1992-02-01 00:00:00

  • Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer.

    abstract::Mutations in the p53 gene have been implicated to play an important role in the development of various human cancers. To evaluate the importance of p53 in lung cancer, a transgenic mouse model was established by utilizing the Clara cell secretory protein (CCSP) promoter to target the expression of a dominant-negative ...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.27.2.4799

    authors: Tchou-Wong KM,Jiang Y,Yee H,LaRosa J,Lee TC,Pellicer A,Jagirdar J,Gordon T,Goldberg JD,Rom WN

    更新日期:2002-08-01 00:00:00

  • The Diacetyl-Exposed Human Airway Epithelial Secretome: New Insights into Flavoring-Induced Airways Disease.

    abstract::Bronchiolitis obliterans (BO) is an increasingly important lung disease characterized by fibroproliferative airway lesions and decrements in lung function. Occupational exposure to the artificial food flavoring ingredient diacetyl, commonly used to impart a buttery flavor to microwave popcorn, has been associated with...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2016-0372OC

    authors: Brass DM,Gwinn WM,Valente AM,Kelly FL,Brinkley CD,Nagler AE,Moseley MA,Morgan DL,Palmer SM,Foster MW

    更新日期:2017-06-01 00:00:00

  • Betamethasone activation of CTP:cholinephosphate cytidylyltransferase in vivo is lipid dependent.

    abstract::Glucocorticoids increase surfactant phosphatidylcholine synthesis, in part, by stimulating the rate regulatory enzyme CTP:cholinephosphate cytidylyltransferase. This enzyme exists in mammalian lung cytosol as an active lipoprotein form (H-form) and an inactive apoprotein (L-form) species. We administered betamethasone...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.10.1.8292380

    authors: Mallampalli RK,Walter ME,Peterson MW,Hunninghake GW

    更新日期:1994-01-01 00:00:00

  • Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation.

    abstract::Zn may have an important protective role in the respiratory epithelium and Zn deficiency may enhance airway inflammation and epithelial damage. The effects of mild nutritional Zn deficiency on airway hyperresponsiveness (AHR) and airway inflammation in mice sensitized and challenged with ovalbumin (OVA) to induce an a...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2001-0014OC

    authors: Truong-Tran AQ,Ruffin RE,Foster PS,Koskinen AM,Coyle P,Philcox JC,Rofe AM,Zalewski PD

    更新日期:2002-09-01 00:00:00

  • Respirable coal dust particles modify cytochrome P4501A1 (CYP1A1) expression in rat alveolar cells.

    abstract::Cytochrome P4501A1 (CYP1A1) metabolizes polycyclic aromatic hydrocarbons in cigarette smoke to DNA-binding reactive intermediates associated with carcinogenesis. Epidemiologic studies indicate that the majority of coal miners are smokers but have a lower risk of lung cancer than other smokers. We hypothesized that coa...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2003-0425OC

    authors: Ghanem MM,Porter D,Battelli LA,Vallyathan V,Kashon ML,Ma JY,Barger MW,Nath J,Castranova V,Hubbs AF

    更新日期:2004-08-01 00:00:00