Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension

详细信息    查看全文

• 作者：Jasmin Wellbrock ; Lars Harbaum ; Hauke Stamm ; Jan K. Hennigs ; Bj?rn Schulz…
• 关键词：Pulmonary arterial hypertension ; Bone morphogenetic protein ; BMPR2 ; Biomarker ; BMP antagonists ; Gremlin ; 1
• 刊名：Lung
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：193
• 期：4
• 页码：567-570
• 全文大小：422 KB
• 参考文献：1.Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 122:4306-313PubMed Central PubMed View Article
  2.Hamid R, Cogan JD, Hedges LK et al (2009) Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum Mutat 30:649-54PubMed Central PubMed View Article
  3.Costello CM, Howell K, Cahill E et al (2008) Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295:L272–L284PubMed View Article
  4.Cahill E, Costello CM, Rowan SC et al (2012) Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation 125:920-30PubMed View Article
  5.Ciuclan L, Sheppard K, Dong L et al (2013) Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice. Am J Pathol 183:1461-473PubMed View Article
  6.Simonneau G, Gatzoulis MA, Adatia I et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34–D41PubMed View Article
  7.Mitola S, Ravelli C, Moroni E et al (2010) Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116:3677-680PubMed View Article
  8.Stabile H, Mitola S, Moroni E et al (2007) Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood 109:1834-840PubMed View Article
  9.Maciel TT, Melo RS, Schor N et al (2008) Gremlin promotes vascular smooth muscle cell proliferation and migration. J Mol Cell Cardiol 44:370-79PubMed View Article
  10.Ito A, Egashira K, Kadokami T et al (1995) Chronic inhibition of endothelium-derived nitric oxide synthesis uses coronary microvascular structural changes and hyperreactivity to serotonin in pigs. Circulation 92:2636-644PubMed View Article
  11.Gangopahyay A, Oran M, Bauer EM et al (2011) Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation. J Biol Chem 286:33134-3140PubMed Central PubMed View Article
  12.Maruyama H, Dewachter C, Belhaj A et al (2014) Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension. J Heart Lung Transplant S1053-2498:01346-1
  13.Mueller KA, Tavlaki E, Schneider M et al (2013) Gremlin-1 identifies fibrosis and predicts adverse outcome in patients with heart failure undergoing endomyocardial biopsy. J Card Fail 19:678-84PubMed View Article
  14.O’Reilly S, Ciechomska M, Cant R et al (2014) Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J Biol Chem 289:9952-960PubMed Central PubMed View Article
  15.Wellbrock J, Sheikhzadeh S, Oliveira-Ferrer L et al (2014) Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. PLoS One 9:e104742PubMed Central PubMed View Article
  
• 作者单位：Jasmin Wellbrock (1)
  Lars Harbaum (1)
  Hauke Stamm (1)
  Jan K. Hennigs (1)
  Bj?rn Schulz (1)
  Hans Klose (1)
  Carsten Bokemeyer (1)
  Walter Fiedler (1)
  Nicole Lüneburg (2)
  
  1. Department of Hematology, Oncology and Stem Cell Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  2. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pneumology and Respiratory System
  
• 出版者：Springer New York
• ISSN：1432-1750

文摘

Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients-functional status and outcome. With a mean level of 242?±?24?ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151?±?18?ng/ml in 15 age- and gender-matched healthy subject (p?=?0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r?=?0.608, p?<?0.001) and inversely with the 6-minute walking distance (r?=??.412, p?=?0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p?=?0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients-functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling.