Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure

E.D. van Deel; M. Snelders; N. van Vliet; L. Te Riet; T.P.P. van den Bosch; L.R. Fiedler; A.C.C. van Spreeuwel; N.A.M. Bax; N. Boontje; C.M. Halabi; T. Sasaki; D.P. Reinhardt; J. van der Velden; C.V.C. Bouten; J.H. von der Thüsen; A.H.J. Danser; D.J. Duncker; M.D. Schneider; I. van der Pluijm; J. Essers

doi:10.1038/s42003-025-08087-8

Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure

E.D. van Deel
, M. Snelders
, N. van Vliet
, L. Te Riet
, T.P.P. van den Bosch
, L.R. Fiedler
, A.C.C. van Spreeuwel
, N.A.M. Bax
, N. Boontje
, C.M. Halabi
, T. Sasaki
, D.P. Reinhardt
, J. van der Velden
, C.V.C. Bouten
, J.H. von der Thüsen
, A.H.J. Danser
, D.J. Duncker
, M.D. Schneider
, I. van der Pluijm
, J. Essers (Corresponding author-nrf)

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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 +/+) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4 +/R 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 +/R 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.

Original language	English
Article number	661
Number of pages	16
Journal	Communications biology
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s42003-025-08087-8
Publication status	Published - 24 Apr 2025

Bibliographical note

Funding

The authors would like to thank Ingrid van den Berg\u2013Garrelds for her measurements of the plasma renin concentrations in fibulin-4 and fibulin-4 mice. This work was supported by the \u201CUNESCO-L\u2019Or\u00E9al for Woman in Science Fellowship\u201D (E.D.D.), the Netherlands Institute for Regenerative medicine (FES0908, A.C.C.S., N.A.M.B and C.V.C.B.), Genetic Aortic Disorders Association Canada and Natural Sciences and Engineering Research Council of Canada (D.P.R.), the British Heart Foundation Centre of Research Excellence and British Heart Foundation Simon Marks Chair in Regenerative Cardiology (M.D.S.), the \u201CLijf en Leven\u201D-grant (2008): \u201CEarly detection and diagnosis of aneurysms and heart valve abnormalities\u201D (J.E.) and Dilating versus Stenosing arterial disease (2011) (E.D.D., I.P., and J.E.), the HeartCHIP II Health~Holland project (grant number EMCLSH19005, M.S.), the Dutch CardioVascular Alliance, an initiative with financial support of the Dutch Heart Foundation (2017B018-ARENA-PRIME & 2021B008-RECONNEXT, D.J.D.), and TKI-LSH grant Quantitative in vivo imaging of heart failure (HF-Image, LSHM18002, N.V.).

Keywords

Animals
Cardiomegaly/metabolism
Mice
Heart Failure/metabolism
Extracellular Matrix Proteins/metabolism
Mice, Inbred C57BL
Myocardium/metabolism
Male
Myocytes, Cardiac/metabolism

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van Deel, E. D., Snelders, M., van Vliet, N., Te Riet, L., van den Bosch, T. P. P., Fiedler, L. R., van Spreeuwel, A. C. C., Bax, N. A. M., Boontje, N., Halabi, C. M., Sasaki, T., Reinhardt, D. P., van der Velden, J., Bouten, C. V. C., von der Thüsen, J. H., Danser, A. H. J., Duncker, D. J., Schneider, M. D., van der Pluijm, I., & Essers, J. (2025). Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure. Communications biology, 8(1), Article 661. https://doi.org/10.1038/s42003-025-08087-8

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title = "Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure",

abstract = "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 +/+) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4 +/R 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 +/R 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. ",

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doi = "10.1038/s42003-025-08087-8",

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van Deel, ED, Snelders, M, van Vliet, N, Te Riet, L, van den Bosch, TPP, Fiedler, LR, van Spreeuwel, ACC, Bax, NAM, Boontje, N, Halabi, CM, Sasaki, T, Reinhardt, DP, van der Velden, J, Bouten, CVC, von der Thüsen, JH, Danser, AHJ, Duncker, DJ, Schneider, MD, van der Pluijm, I & Essers, J 2025, 'Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure', Communications biology, vol. 8, no. 1, 661. https://doi.org/10.1038/s42003-025-08087-8

TY - JOUR

T1 - Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure

AU - van Deel, E.D.

AU - Snelders, M.

AU - van Vliet, N.

AU - Te Riet, L.

AU - van den Bosch, T.P.P.

AU - Fiedler, L.R.

AU - van Spreeuwel, A.C.C.

AU - Bax, N.A.M.

AU - Boontje, N.

AU - Halabi, C.M.

AU - Sasaki, T.

AU - Reinhardt, D.P.

AU - van der Velden, J.

AU - Bouten, C.V.C.

AU - von der Thüsen, J.H.

AU - Danser, A.H.J.

AU - Duncker, D.J.

AU - Schneider, M.D.

AU - van der Pluijm, I.

A2 - Essers, J.

PY - 2025/4/24

Y1 - 2025/4/24

N2 - 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 +/+) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4 +/R 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 +/R 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.

AB - 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 +/+) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4 +/R 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 +/R 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.

KW - Animals

KW - Cardiomegaly/metabolism

KW - Mice

KW - Heart Failure/metabolism

KW - Extracellular Matrix Proteins/metabolism

KW - Mice, Inbred C57BL

KW - Myocardium/metabolism

KW - Male

KW - Myocytes, Cardiac/metabolism

UR - https://www.scopus.com/pages/publications/105003464461

U2 - 10.1038/s42003-025-08087-8

DO - 10.1038/s42003-025-08087-8

M3 - Article

C2 - 40274989

SN - 2399-3642

VL - 8

JO - Communications biology

JF - Communications biology

IS - 1

M1 - 661

ER -

Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure

Abstract

Bibliographical note

Funding

Keywords

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