Acid sphingomyelinase promotes SGK1-dependent vascular calcification

Area of Science:

• Biochemistry
• Cell Biology
• Cardiovascular Research

Background:

• Hyperphosphatemia in chronic kidney disease (CKD) drives medial vascular calcification, increasing cardiovascular risk.
• Vascular calcification involves smooth muscle cell transdifferentiation, but underlying signaling is unclear.

Purpose of the Study:

• Investigate the role of acid sphingomyelinase (ASM) and ceramide in vascular smooth muscle cell (VSMC) calcification.
• Determine if ASM/ceramide signaling impacts VSMC calcification pathways, including SGK1.

Main Methods:

• In vitro studies using VSMCs treated with bacterial sphingomyelinase, phosphate, and ceramide.
• In vivo studies using a mouse model of vascular calcification and ex vivo perfused arteries.
• Genetic manipulation (ASM deficiency, SGK1 silencing) and pharmacological inhibition of ASM.

Main Results:

• ASM activation and ceramide increased VSMC calcification, partly via SGK1.
• ASM deficiency reduced vascular calcification in mice and cultured VSMCs.
• ASM inhibitors (amitriptyline, fendiline) suppressed calcification pathways both in vitro and in vivo.

Conclusions:

• ASM/ceramide acts as a key upstream regulator of vascular calcification in CKD.
• ASM inhibition, potentially via repurposed drugs, could be a therapeutic strategy to slow vascular calcification progression.