Sphingolipids in atherosclerosis and vascular biology

Area of Science:

• Vascular Biology
• Lipid Metabolism
• Cell Signaling

Background:

• Sphingolipids and their metabolites act as second messengers in cellular signaling.
• Lactosylceramide (LacCer), a glycosphingolipid (GSL) in vascular cells, accumulates in atherosclerotic plaques.
• Oxidized low-density lipoproteins (Ox-LDLs) specifically stimulate LacCer biosynthesis, linking it to atherosclerosis.

Purpose of the Study:

• To elucidate the role of LacCer in vascular cell proliferation and signaling pathways.
• To investigate the mechanisms by which LacCer contributes to atherosclerosis.
• To explore the potential of targeting sphingolipid metabolism for atherosclerosis therapy.

Main Methods:

• In vitro studies using aortic smooth muscle cells (ASMCs) and vascular endothelial cells.
• Investigating the signaling cascade initiated by LacCer, including NADPH oxidase activation and MAPK pathway.
• Utilizing inhibitors like D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) and antibodies against neutral sphingomyelinase (N-SMase).

Main Results:

• LacCer stimulates ASMC proliferation via activation of NADPH oxidase, p21(ras), and the MAPK cascade (Raf-1, Mek2, p44MAPK).
• LacCer mediates TNF-alpha-induced expression of NF-kappaB and ICAM-1 in endothelial cells, and CD11/CD8 (Mac-1) on neutrophils, promoting cell adhesion.
• Neutral sphingomyelinase (N-SMase) activation by cytokines and Ox-LDL induces apoptosis, potentially contributing to plaque instability.

Conclusions:

• LacCer is a key mediator in atherosclerosis, driving vascular cell proliferation and adhesion.
• Targeting LacCer synthesis or N-SMase activity presents potential therapeutic avenues for atherosclerosis.
• Sphingolipid metabolism plays a critical role in vascular disease, offering opportunities for novel treatments.