Acid sphingomyelinase promotes SGK1-dependent vascular calcification. Issue 3 (12th February 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Clinical science. Volume 135:Issue 3(2021)
• Page Start: 515
• Page End: 534
• Publication Date: 2021-02-12
• Subjects: acid sphingomyelinase -- ceramide -- serum- and glucocorticoid-inducible kinase 1 -- vascular calcification -- vascular smooth muscle cells -- phosphate; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20201122
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: 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.