Acid sphingomyelinase promotes SGK1-dependent vascular calcification.

Autor:	Luong TTD; Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria., Tuffaha R; Department of Physiology I, Eberhard-Karls University, Tübingen, Germany., Schuchardt M; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Moser B; Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria., Schelski N; Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany., Boehme B; Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany., Gollmann-Tepeköylü C; University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria., Schramm C; Division of Pathophysiology, Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria., Holfeld J; University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria., Pieske B; Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.; Department of Internal Medicine and Cardiology, German Heart Center Berlin (DHZB), Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany., Gulbins E; Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Tölle M; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., van der Giet M; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Lang F; Department of Physiology I, Eberhard-Karls University, Tübingen, Germany., Eckardt KU; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Voelkl J; Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria.; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany., Alesutan I; Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria.
Jazyk:	angličtina
Zdroj:	Clinical science (London, England : 1979) [Clin Sci (Lond)] 2021 Feb 12; Vol. 135 (3), pp. 515-534.
DOI:	10.1042/CS20201122
Abstrakt:	In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study. (© 2021 The Author(s).)
Databáze:	MEDLINE
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