Small-molecule-induced ERBB4 activation to treat heart failure
Abstract Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize tha...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54908-5 |
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| author | Julie M. T. Cools Bo K. Goovaerts Eline Feyen Siel Van den Bogaert Yile Fu Céline Civati Jens Van fraeyenhove Michiel R. L. Tubeeckx Jasper Ott Long Nguyen Eike M. Wülfers Benji Van Berlo Antoine A. F. De Vries Nele Vandersickel Daniël A. Pijnappels Dominique Audenaert H. Llewelyn Roderick Hans De Winter Gilles W. De Keulenaer Vincent F. M. Segers |
| author_facet | Julie M. T. Cools Bo K. Goovaerts Eline Feyen Siel Van den Bogaert Yile Fu Céline Civati Jens Van fraeyenhove Michiel R. L. Tubeeckx Jasper Ott Long Nguyen Eike M. Wülfers Benji Van Berlo Antoine A. F. De Vries Nele Vandersickel Daniël A. Pijnappels Dominique Audenaert H. Llewelyn Roderick Hans De Winter Gilles W. De Keulenaer Vincent F. M. Segers |
| author_sort | Julie M. T. Cools |
| collection | DOAJ |
| description | Abstract Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize that small-molecule activation of ERBB4 could protect against heart damage and fibrosis. To test this, we conduct a screening of 10,240 compounds and identify eight structurally similar ones (EF-1 to EF-8) that induce ERBB4 dimerization, with EF-1 being the most effective. EF-1 reduces cell death and hypertrophy in cardiomyocytes and decreases collagen production in cardiac fibroblasts in an ERBB4-dependent manner. In wild-type mice, EF-1 inhibits angiotensin-II-induced fibrosis in males and females and reduces heart damage caused by doxorubicin and myocardial infarction in females, but not in Erbb4-null mice. This study shows that small-molecule ERBB4 activation is feasible and may lead to a novel class of drugs for treating heart failure. |
| format | Article |
| id | doaj-art-e8e46c0841a143a99b316fc5a47e03d8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e8e46c0841a143a99b316fc5a47e03d82025-01-12T12:31:59ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-54908-5Small-molecule-induced ERBB4 activation to treat heart failureJulie M. T. Cools0Bo K. Goovaerts1Eline Feyen2Siel Van den Bogaert3Yile Fu4Céline Civati5Jens Van fraeyenhove6Michiel R. L. Tubeeckx7Jasper Ott8Long Nguyen9Eike M. Wülfers10Benji Van Berlo11Antoine A. F. De Vries12Nele Vandersickel13Daniël A. Pijnappels14Dominique Audenaert15H. Llewelyn Roderick16Hans De Winter17Gilles W. De Keulenaer18Vincent F. M. Segers19Laboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU LeuvenLaboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of Cell Biology and Histology, University of AntwerpScreening Core, VIBDepartment of Physics and Astronomy, Ghent UniversityLaboratory of PhysioPharmacology, University of AntwerpLaboratory of Experimental Cardiology, Leiden University Medical CenterDepartment of Physics and Astronomy, Ghent UniversityLaboratory of Experimental Cardiology, Leiden University Medical CenterScreening Core, VIBLaboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU LeuvenLaboratory of Medicinal Chemistry, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpLaboratory of PhysioPharmacology, University of AntwerpAbstract Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize that small-molecule activation of ERBB4 could protect against heart damage and fibrosis. To test this, we conduct a screening of 10,240 compounds and identify eight structurally similar ones (EF-1 to EF-8) that induce ERBB4 dimerization, with EF-1 being the most effective. EF-1 reduces cell death and hypertrophy in cardiomyocytes and decreases collagen production in cardiac fibroblasts in an ERBB4-dependent manner. In wild-type mice, EF-1 inhibits angiotensin-II-induced fibrosis in males and females and reduces heart damage caused by doxorubicin and myocardial infarction in females, but not in Erbb4-null mice. This study shows that small-molecule ERBB4 activation is feasible and may lead to a novel class of drugs for treating heart failure.https://doi.org/10.1038/s41467-024-54908-5 |
| spellingShingle | Julie M. T. Cools Bo K. Goovaerts Eline Feyen Siel Van den Bogaert Yile Fu Céline Civati Jens Van fraeyenhove Michiel R. L. Tubeeckx Jasper Ott Long Nguyen Eike M. Wülfers Benji Van Berlo Antoine A. F. De Vries Nele Vandersickel Daniël A. Pijnappels Dominique Audenaert H. Llewelyn Roderick Hans De Winter Gilles W. De Keulenaer Vincent F. M. Segers Small-molecule-induced ERBB4 activation to treat heart failure Nature Communications |
| title | Small-molecule-induced ERBB4 activation to treat heart failure |
| title_full | Small-molecule-induced ERBB4 activation to treat heart failure |
| title_fullStr | Small-molecule-induced ERBB4 activation to treat heart failure |
| title_full_unstemmed | Small-molecule-induced ERBB4 activation to treat heart failure |
| title_short | Small-molecule-induced ERBB4 activation to treat heart failure |
| title_sort | small molecule induced erbb4 activation to treat heart failure |
| url | https://doi.org/10.1038/s41467-024-54908-5 |
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