Acid sphingomyelinase promotes SGK1-dependent vascular calcification

• Published in: Clinical science (1979) Vol. 135; no. 3; pp. 515 - 534
• Main Authors: Luong, Trang Thi Doan, Tuffaha, Rashad, Schuchardt, Mirjam, Moser, Barbara, Schelski, Nadeshda, Boehme, Beate, Gollmann-Tepeköylü, Can, Schramm, Clara, Holfeld, Johannes, Pieske, Burkert, Gulbins, Erich, Tölle, Markus, van der Giet, Markus, Lang, Florian, Eckardt, Kai-Uwe, Voelkl, Jakob, Alesutan, Ioana
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 12.02.2021
• Subjects: Cardiovascular System & Vascular Biology; Cell Death & Injury; Gene Expression & Regulation; Signaling; phosphate; ceramide; vascular smooth muscle cells; acid sphingomyelinase; vascular calcification; serum- and glucocorticoid-inducible kinase 1
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20201122

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.