Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production

Daigo Sawaki, Gabor Czibik, Maria Pini, Julien Ternacle, Nadine Suffee, Raquel Mercedes, Geneviève Marcelin, Mathieu Surenaud, Elisabeth Marcos, Philippe Gual, Karine Clément, Sophie Hue, Serge Adnot, Stéphane N. Hatem, Izuru Tsuchimochi, Takehiko Yoshimitsu, Corneliu Hénégar, Geneviève Derumeaux

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28 Citations (Scopus)

Abstract

BACKGROUND: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. METHODS: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). RESULTS: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor β levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. CONCLUSIONS: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN's role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

Original languageEnglish
Pages (from-to)809-822
Number of pages14
JournalCirculation
Volume138
Issue number8
DOIs
Publication statusPublished - 2018

Keywords

  • Adipokines
  • Adipose tissue
  • Aging
  • Cellular senescence
  • Fibrosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Sawaki, D., Czibik, G., Pini, M., Ternacle, J., Suffee, N., Mercedes, R., Marcelin, G., Surenaud, M., Marcos, E., Gual, P., Clément, K., Hue, S., Adnot, S., Hatem, S. N., Tsuchimochi, I., Yoshimitsu, T., Hénégar, C., & Derumeaux, G. (2018). Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production. Circulation, 138(8), 809-822. https://doi.org/10.1161/CIRCULATIONAHA.117.031358