Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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.

MeSH terms

Substances

LinkOut - more resources