Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure
The prevailing view of fibulin-4 deficient mice is that the cardiac phenotype is the result of aortic and/or valvular disease. In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-4<sup>+/+</sup>) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4<sup>+/R</sup> mice exposed to severe TAC do not show this increase in myocardial fibulin-4 expression, but display altered physical properties of myocardial tissue. Moreover, TAC-induced cardiac fibrosis, pulmonary congestion, and mortality are aggravated in fibulin-4<sup>+/R</sup> mice. In vitro investigations of myocardial tissue show that fibulin-4 deficiency results in cardiomyocyte hypertrophy, and a decreased beating frequency and contractile force. In conclusion, we demonstrate functions for fibulin-4 in cardiac homeostasis and show that reduced fibulin-4 expression drives myocardial disease in response to cardiac pressure overload, independent of aortic valvular pathology.
Authors
- Luuk te Riet
- Jan H. von der Thüsen (ORCID: https://orcid.org/0000-0001-9699-4860)
- Lorna R. Fiedler (ORCID: https://orcid.org/0000-0003-3118-6410)
- Ariane C. C. van Spreeuwel
- Nicky M. Boontje
- Matthijs Snelders (ORCID: https://orcid.org/0000-0002-6306-9270)
- Nicole van Vliet
- Carlijn V. C. Bouten (ORCID: https://orcid.org/0000-0003-1035-5094)
- Ingrid van der Pluijm (ORCID: https://orcid.org/0000-0002-9368-5779)
- Takako Sasaki (ORCID: https://orcid.org/0000-0003-0514-9931)
- A.H. Jan Danser (ORCID: https://orcid.org/0000-0002-5052-3585)
- Michael Schneider (ORCID: https://orcid.org/0000-0001-9645-1938)
- Thierry P. P. van den Bosch
- Carmen M. Halabi (ORCID: https://orcid.org/0000-0003-4889-8131)
- Noortje A.M. Bax (ORCID: https://orcid.org/0000-0002-3602-6400)
- Elza D. van Deel (ORCID: https://orcid.org/0000-0001-5548-2631)
- Dirk Jan Duncker (ORCID: https://orcid.org/0000-0003-2836-2241)
- Jeroen Essers (ORCID: https://orcid.org/0000-0003-0605-7211)
- Jacobus van der Velden (ORCID: https://orcid.org/0000-0002-5985-1163)
- Dieter P. Reinhardt (ORCID: https://orcid.org/0000-0001-6535-9872)
Institutions
- Oita University (JP)
- Washington University in St. Louis (US)
- McGill University Health Centre (CA)
- Erasmus MC (NL)
- British Heart Foundation (GB)
- Imperial College London (GB)
- Eindhoven University of Technology (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s42003-025-08087-8
- Citations
- 1
- Primary Topic
- Connective tissue disorders research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- L'Oreal USA
- Health~Holland
- Dutch Cardiovascular Alliance
- British Heart Foundation
- Natural Sciences and Engineering Research Council of Canada