Theranostics 2020; 10(9):3905-3924. doi:10.7150/thno.38640 This issue Cite

Research Paper

Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1

Tim Wilhelmi1,3*, Xingbo Xu1,3*, Xiaoying Tan2,3, Melanie S. Hulshoff1,3,4, Sabine Maamari1,3, Samuel Sossalla1,3,5, Michael Zeisberg2,3, Elisabeth M. Zeisberg1,3✉

1. Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
2. Department of Nephrology and Rheumatology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
3. DZHK (German Centre for Cardiovascular Research, partner site Göttingen, Germany).
4. Laboratory for Cardiovascular Regenerative Medicine, Department of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands.
5. Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
*These authors contributed equally to this work.

Citation:
Wilhelmi T, Xu X, Tan X, Hulshoff MS, Maamari S, Sossalla S, Zeisberg M, Zeisberg EM. Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. Theranostics 2020; 10(9):3905-3924. doi:10.7150/thno.38640. https://www.thno.org/v10p3905.htm
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Abstract

Graphic abstract

Rationale: Cardiac fibrosis is an integral constituent of every form of chronic heart disease, and persistence of fibrosis reduces tissue compliance and accelerates the progression to heart failure. Relaxin-2 is a human hormone, which has various physiological functions such as mediating renal vasodilation in pregnancy. Its recombinant form Serelaxin has recently been tested in clinical trials as a therapy for acute heart failure but did not meet its primary endpoints. The aim of this study is to examine whether Serelaxin has an anti-fibrotic effect in the heart and therefore could be beneficial in chronic heart failure.

Methods: We utilized two different cardiac fibrosis mouse models (ascending aortic constriction (AAC) and Angiotensin II (ATII) administration via osmotic minipumps) to assess the anti-fibrotic potential of Serelaxin. Histological analysis, immunofluorescence staining and molecular analysis were performed to assess the fibrosis level and indicate endothelial cells which are undergoing EndMT. In vitro TGFβ1-induced endothelial-to-mesenchymal transition (EndMT) assays were performed in human coronary artery endothelial cells and mouse cardiac endothelial cells (MCECs) and were examined using molecular methods. Chromatin immunoprecipitation-qPCR assay was utilized to identify the Serelaxin effect on chromatin remodeling in the Rxfp1 promoter region in MCECs.

Results: Our results demonstrate a significant and dose-dependent anti-fibrotic effect of Serelaxin in the heart in both models. We further show that Serelaxin mediates this effect, at least in part, through inhibition of EndMT through the endothelial Relaxin family peptide receptor 1 (RXFP1). We further demonstrate that Serelaxin administration is able to increase its own receptor expression (RXFP1) through epigenetic regulation in form of histone modifications by attenuating TGFβ-pSMAD2/3 signaling in endothelial cells.

Conclusions: This study is the first to identify that Serelaxin increases the expression of its own receptor RXFP1 and that this mediates the inhibition of EndMT and cardiac fibrosis, suggesting that Serelaxin may have a beneficial effect as anti-fibrotic therapy in chronic heart failure.

Keywords: Serelaxin, EndMT, fibrosis, Notch, histone methylation


Citation styles

APA
Wilhelmi, T., Xu, X., Tan, X., Hulshoff, M.S., Maamari, S., Sossalla, S., Zeisberg, M., Zeisberg, E.M. (2020). Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. Theranostics, 10(9), 3905-3924. https://doi.org/10.7150/thno.38640.

ACS
Wilhelmi, T.; Xu, X.; Tan, X.; Hulshoff, M.S.; Maamari, S.; Sossalla, S.; Zeisberg, M.; Zeisberg, E.M. Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. Theranostics 2020, 10 (9), 3905-3924. DOI: 10.7150/thno.38640.

NLM
Wilhelmi T, Xu X, Tan X, Hulshoff MS, Maamari S, Sossalla S, Zeisberg M, Zeisberg EM. Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. Theranostics 2020; 10(9):3905-3924. doi:10.7150/thno.38640. https://www.thno.org/v10p3905.htm

CSE
Wilhelmi T, Xu X, Tan X, Hulshoff MS, Maamari S, Sossalla S, Zeisberg M, Zeisberg EM. 2020. Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. Theranostics. 10(9):3905-3924.

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