Abstract
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 = −0.412, 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.
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References
Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 122:4306–4313
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 30:649–654
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–L284
Cahill E, Costello CM, Rowan SC et al (2012) Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation 125:920–930
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 183:1461–1473
Simonneau G, Gatzoulis MA, Adatia I et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34–D41
Mitola S, Ravelli C, Moroni E et al (2010) Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116:3677–3680
Stabile H, Mitola S, Moroni E et al (2007) Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood 109:1834–1840
Maciel TT, Melo RS, Schor N et al (2008) Gremlin promotes vascular smooth muscle cell proliferation and migration. J Mol Cell Cardiol 44:370–379
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 92:2636–2644
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 286:33134–33140
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
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 19:678–684
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 289:9952–9960
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:e104742
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Medical Faculty of the University of Hamburg (FFM program).
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Jasmin Wellbrock and Lars Harbaum contributed equally.
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Wellbrock, J., Harbaum, L., Stamm, H. et al. Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension. Lung 193, 567–570 (2015). https://doi.org/10.1007/s00408-015-9735-5
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DOI: https://doi.org/10.1007/s00408-015-9735-5