Regulation of adverse remodelling by osteopontin in a genetic heart failure model

Stelios Psarras, Manolis Mavroidis, Despina Sanoudou, Constantinos H. Davos, Georgina Xanthou, Aimilia E. Varela, Vily Panoutsakopoulou, Yassemi Capetanaki

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Aims Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des-/-) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des-/- mice and their potential link to OPN. Methods and resultsIn situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des-/- myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des-/-OPN-/- mice and compared their cardiac function and remodelling indices with those of des-/-. Osteopontin promoted cardiac dysfunction in this model since des -/-OPN-/- mice showed 53 improvement of left ventricular function, paralleled to an up to 44 reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. ConclusionCardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des-/- adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.

Original languageEnglish
Pages (from-to)1954-1963
Number of pages10
JournalEuropean Heart Journal
Volume33
Issue number15
DOIs
Publication statusPublished - 1 Aug 2012
Externally publishedYes

Fingerprint

Osteopontin
Desmin
Heart Failure
Galectin 3
Fibrosis
Macrophages
Intermediate Filament Proteins
Dilated Cardiomyopathy
Metalloproteases
Left Ventricular Function
Cardiac Myocytes
Innate Immunity
Myocardium
Histology
Up-Regulation
RNA
Pathology
Inflammation

Keywords

  • Cardiomyopathy
  • Desmin
  • Fibrosis
  • Galectin-3
  • Heart failure
  • Myocardial inflammation
  • Osteopontin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Psarras, S., Mavroidis, M., Sanoudou, D., Davos, C. H., Xanthou, G., Varela, A. E., ... Capetanaki, Y. (2012). Regulation of adverse remodelling by osteopontin in a genetic heart failure model. European Heart Journal, 33(15), 1954-1963. https://doi.org/10.1093/eurheartj/ehr119

Regulation of adverse remodelling by osteopontin in a genetic heart failure model. / Psarras, Stelios; Mavroidis, Manolis; Sanoudou, Despina; Davos, Constantinos H.; Xanthou, Georgina; Varela, Aimilia E.; Panoutsakopoulou, Vily; Capetanaki, Yassemi.

In: European Heart Journal, Vol. 33, No. 15, 01.08.2012, p. 1954-1963.

Research output: Contribution to journalArticle

Psarras, S, Mavroidis, M, Sanoudou, D, Davos, CH, Xanthou, G, Varela, AE, Panoutsakopoulou, V & Capetanaki, Y 2012, 'Regulation of adverse remodelling by osteopontin in a genetic heart failure model', European Heart Journal, vol. 33, no. 15, pp. 1954-1963. https://doi.org/10.1093/eurheartj/ehr119
Psarras S, Mavroidis M, Sanoudou D, Davos CH, Xanthou G, Varela AE et al. Regulation of adverse remodelling by osteopontin in a genetic heart failure model. European Heart Journal. 2012 Aug 1;33(15):1954-1963. https://doi.org/10.1093/eurheartj/ehr119
Psarras, Stelios ; Mavroidis, Manolis ; Sanoudou, Despina ; Davos, Constantinos H. ; Xanthou, Georgina ; Varela, Aimilia E. ; Panoutsakopoulou, Vily ; Capetanaki, Yassemi. / Regulation of adverse remodelling by osteopontin in a genetic heart failure model. In: European Heart Journal. 2012 ; Vol. 33, No. 15. pp. 1954-1963.
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abstract = "Aims Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des-/-) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des-/- mice and their potential link to OPN. Methods and resultsIn situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des-/- myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des-/-OPN-/- mice and compared their cardiac function and remodelling indices with those of des-/-. Osteopontin promoted cardiac dysfunction in this model since des -/-OPN-/- mice showed 53 improvement of left ventricular function, paralleled to an up to 44 reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. ConclusionCardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des-/- adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.",
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AU - Xanthou, Georgina

AU - Varela, Aimilia E.

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N2 - Aims Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des-/-) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des-/- mice and their potential link to OPN. Methods and resultsIn situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des-/- myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des-/-OPN-/- mice and compared their cardiac function and remodelling indices with those of des-/-. Osteopontin promoted cardiac dysfunction in this model since des -/-OPN-/- mice showed 53 improvement of left ventricular function, paralleled to an up to 44 reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. ConclusionCardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des-/- adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.

AB - Aims Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des-/-) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des-/- mice and their potential link to OPN. Methods and resultsIn situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des-/- myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des-/-OPN-/- mice and compared their cardiac function and remodelling indices with those of des-/-. Osteopontin promoted cardiac dysfunction in this model since des -/-OPN-/- mice showed 53 improvement of left ventricular function, paralleled to an up to 44 reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. ConclusionCardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des-/- adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.

KW - Cardiomyopathy

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KW - Fibrosis

KW - Galectin-3

KW - Heart failure

KW - Myocardial inflammation

KW - Osteopontin

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