Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition

Louk T Timmer; Elvira den Hertog; Danielle Versteeg; Harm Post; Job A J Verdonschot; Jantine Monshouwer-Kloots; Eirini Kyriakopoulou; Ilaria Perini; Tim Koopmans; Petra van der Kraak; Lorena Zentilin; Stephane R B Heymans; Aryan Vink; Mauro Giacca; Albert J R Heck; Eva van Rooij

doi:10.1093/cvr/cvaf021

Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition

Louk T Timmer
, Elvira den Hertog
, Danielle Versteeg
, Harm Post
, Job A J Verdonschot
, Jantine Monshouwer-Kloots
, Eirini Kyriakopoulou
, Ilaria Perini
, Tim Koopmans
, Petra van der Kraak
, Lorena Zentilin
, Stephane R B Heymans
, Aryan Vink
, Mauro Giacca
, Albert J R Heck
, Eva van Rooij^*

^*Corresponding author for this work

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

Abstract

Aims In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice. Methods and results Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin–cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling. Conclusion Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

Original language	English
Pages (from-to)	585-600
Number of pages	16
Journal	Cardiovascular Research
Volume	121
Issue number	4
Early online date	17 Feb 2025
DOIs	https://doi.org/10.1093/cvr/cvaf021
Publication status	Published - Mar 2025

Bibliographical note

Funding

This work was supported by the Dutch CardioVascular Alliance (DCVA), an initiative with support of the Dutch Heart Foundation (DCVA2017-18 ARENA-PRIME) and a Vici grant from the Dutch Research Council (NWO), project 09150181910020 to E.v.R. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University, and The Netherlands X-omics Initiative (NWO project 184.034.019). H.P. and A.J.R.H. acknowledge support from the Netherlands Proteomics Centre, which is subsidized by Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.A.J.V. received a Dekker Clinical Scientist grant from the Dutch Heart Foundation (03-005-2022-0040) and an Academic Funds grant from the Maastricht University Medical Center (MUMC) (00499).

Funders	Funder number
Dutch CardioVascular Alliance (DCVA)
Dutch Heart Foundation	DCVA2017-18 ARENA-PRIME, 03-005-2022-0040
Dutch Research Council (NWO)	09150181910020
University Medical Center Utrecht, Hubrecht Institute, Utrecht University
Netherlands Xomics Initiative (NWO)	184.034.019
Netherlands Proteomics Centre
Academic Funds Maastricht University Medical Center (MUMC)	00499

Keywords

Cardiomyocyte
Extracellular matrix
Heart failure
Integrins
SORBS2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/cvr/cvaf021Licence: CC BY

cvaf021Final published version, 13 MBLicence: CC BY

Cite this

Timmer, L. T., den Hertog, E., Versteeg, D., Post, H., Verdonschot, J. A. J., Monshouwer-Kloots, J., Kyriakopoulou, E., Perini, I., Koopmans, T., van der Kraak, P., Zentilin, L., Heymans, S. R. B., Vink, A., Giacca, M., Heck, A. J. R., & van Rooij, E. (2025). Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition. Cardiovascular Research, 121(4), 585-600. https://doi.org/10.1093/cvr/cvaf021

@article{b8f47b823fe941b2b5baa202dce9ffba,

title = "Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition",

abstract = "Aims In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice. Methods and results Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin–cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling. Conclusion Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.",

keywords = "Cardiomyocyte, Extracellular matrix, Heart failure, Integrins, SORBS2",

author = "Timmer, \{Louk T\} and \{den Hertog\}, Elvira and Danielle Versteeg and Harm Post and Verdonschot, \{Job A J\} and Jantine Monshouwer-Kloots and Eirini Kyriakopoulou and Ilaria Perini and Tim Koopmans and \{van der Kraak\}, Petra and Lorena Zentilin and Heymans, \{Stephane R B\} and Aryan Vink and Mauro Giacca and Heck, \{Albert J R\} and \{van Rooij\}, Eva",

note = "{\textcopyright} The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2025",

month = mar,

doi = "10.1093/cvr/cvaf021",

language = "English",

volume = "121",

pages = "585--600",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "4",

}

Timmer, LT, den Hertog, E, Versteeg, D, Post, H, Verdonschot, JAJ, Monshouwer-Kloots, J, Kyriakopoulou, E, Perini, I, Koopmans, T, van der Kraak, P, Zentilin, L, Heymans, SRB, Vink, A, Giacca, M, Heck, AJR & van Rooij, E 2025, 'Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition', Cardiovascular Research, vol. 121, no. 4, pp. 585-600. https://doi.org/10.1093/cvr/cvaf021

TY - JOUR

T1 - Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition

AU - Timmer, Louk T

AU - den Hertog, Elvira

AU - Versteeg, Danielle

AU - Post, Harm

AU - Verdonschot, Job A J

AU - Monshouwer-Kloots, Jantine

AU - Kyriakopoulou, Eirini

AU - Perini, Ilaria

AU - Koopmans, Tim

AU - van der Kraak, Petra

AU - Zentilin, Lorena

AU - Heymans, Stephane R B

AU - Vink, Aryan

AU - Giacca, Mauro

AU - Heck, Albert J R

AU - van Rooij, Eva

PY - 2025/3

Y1 - 2025/3

N2 - Aims In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice. Methods and results Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin–cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling. Conclusion Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

AB - Aims In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice. Methods and results Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin–cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling. Conclusion Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.

KW - Cardiomyocyte

KW - Extracellular matrix

KW - Heart failure

KW - Integrins

KW - SORBS2

U2 - 10.1093/cvr/cvaf021

DO - 10.1093/cvr/cvaf021

M3 - Article

C2 - 39957251

SN - 0008-6363

VL - 121

SP - 585

EP - 600

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 4

ER -

Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this