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. 2021 Jul;51(7):e13539.
doi: 10.1111/eci.13539. Epub 2021 Mar 17.

Protective role of Gremlin-1 in myocardial function

Iris I Müller  1 , Martina Schneider  1 , Karin A L Müller  1 , Oleg Lunov  2 , Oliver Borst  1 , Thomas Simmet  2 , Meinrad Gawaz  1
Affiliations

Protective role of Gremlin-1 in myocardial function

Iris I Müller et al. Eur J Clin Invest. 2021 Jul.

Abstract

Background: Gremlin-1 is a cystine knot protein and is expressed in organs developing fibrosis. Transient ischaemia leads to myocardial fibrosis, a major determinant of impaired myocardial function.

Materials and methods: Expression of Gremlin-1 was investigated in infarcted myocardium by real-time PCR, Western blot analysis, histological and immunohistochemistry staining. We further elaborated the colocalization of Gremlin-1 and TGF-β proteins by confocal microscopy and co-immunoprecipitation experiments. The interaction between Gremlin-1 and TGF-β was analysed by photon correlation spectroscopy. Gremlin-1 modulation of the TGF-β-dependent collagen I synthesis in fibroblasts was investigated using ELISA and immunohistochemistry experiments. The effect of prolonged administration of recombinant Gremlin-1 on myocardial function following ischaemia/reperfusion was accessed by echocardiography and immunohistochemistry.

Results: Gremlin-1 is expressed in myocardial tissue and infiltrating cells after transient myocardial ischaemia (P < .05). Gremlin-1 colocalizes with the pro-fibrotic cytokine transforming growth factor-β (TGF-β) expressed in fibroblasts and inflammatory cell infiltrates (P < .05). Gremlin-1 reduces TGF-β-induced collagen production of myocardial fibroblasts by approximately 20% (P < .05). We found that Gremlin-1 binds with high affinity to TGF-β (KD = 54 nmol/L) as evidenced by photon correlation spectroscopy and co-immunoprecipitation. intravenous administration of m Gremlin-1-Fc, but not of equivalent amount of Fc control, significantly reduced infarct size by approximately 20%. In the m Gremlin-1-Fc group, infarct area was reduced by up to 30% in comparison with mice treated with Fc control (I/LV: 4.8 ± 1.2% vs 6.0 ± 1.2% P < .05; I/AaR: 15.2 ± 1.5% vs 21.1 ± 5%, P < .05).

Conclusions: The present data disclose Gremlin-1 as an antagonist of TGF-β and presume a role for Gremlin-1/TGF-β interaction in myocardial remodelling following myocardial ischaemia.

Keywords: Gremlin-1; collagen; fibrosis; myocardial infarction; transforming growth factor beta.

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References

REFERENCES

    1. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol. 2010;48(3):504-511.
    1. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51(4):600-606.
    1. Hsu DR, Economides AN, Wang X, Eimon PM, Harland RM. The Xenopus dorsalizing factor gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell. 1998;1(5):673-683.
    1. Topol LZ, Bardot B, Zhang Q, et al. Biosynthesis, post-translation modification, and functional characterization of Drm/Gremlin. J Biol Chem. 2000;275(12):8785-8793.
    1. Rider CC, Mulloy B. Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Biochem J. 2010;429(1):1-12.

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