Daigo Sawaki1, Gabor Czibik1, Maria Pini1, Julien Ternacle1,2, Nadine Suffee3, Raquel Mercedes1, Geneviève Marcelin4,5, Mathieu Surenaud1,6, Elisabeth Marcos1, Philippe Gual7,8, Karine Clément4,5,9, Sophie Hue1,3,6, Serge Adnot1,10, Stéphane N Hatem11, Izuru Tsuchimochi12, Takehiko Yoshimitsu12, Corneliu Hénégar1, Geneviève Derumeaux1,2. 1. INSERM IMRB U955, Université Paris-Est Creteil (D.S., G.C., M.P., J.T., R.M., M.S., E.M., S.H., S.A., C.H., G.D.). 2. AP-HP, Department of Cardiology, Henri Mondor Hospital, DHU-ATVB (J.T., G.D.). 3. Sorbonne Université, INSERM UMRS 1166, Institute of Cardiometabolism and Nutrition ICAN (N.S., S.H.). 4. Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital (G.M., K.C.). 5. Sorbonne Universities, Université Pierre et Marie Curie, University of Paris 06, INSERM UMR_S 1166, Nutriomics Team 6 (G.M., K.C.). 6. AP-HP Vaccine Research Institute (VRI) (M.S., S.H.). 7. INSERM, U1065, C3M, Team 8 "hepatic complications in obesity" (P.G.). 8. Université Côte d'Azur (P.G.). 9. Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department (K.C.). 10. AP-HP, Department of Physiology, Henri Mondor Hospital, DHU-ATVB (S.A.). 11. Institut de Cardiologie, Hôpital Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (S.H.). 12. Laboratory of Synthetic Organic and Medicinal Chemistry, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University (I.T., T.Y.).
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.
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.
Authors: Lindsay T Fourman; Takara L Stanley; Isabel Zheng; Chelsea S Pan; Meghan N Feldpausch; Julia Purdy; Julia Aepfelbacher; Colleen Buckless; Andrew Tsao; Kathleen E Corey; Raymond T Chung; Martin Torriani; David E Kleiner; Colleen M Hadigan; Steven K Grinspoon Journal: Clin Infect Dis Date: 2021-06-15 Impact factor: 9.079