Ceramide in redox signaling and cardiovascular diseases.

Lipid rafts are distinct cell membrane microdomains that consist of cholesterol, sphingolipids, and some associated proteins. Accumulating evidence suggests that activation of sphingomyelinase and generation of ceramide mediates clustering of lipid rafts to form large ceramide-enriched platforms, in which transmembrane signals are transmitted or amplified. Ceramide and reactive oxygen species (ROS) are involved in the modulation of the cell membrane and intracellular ion channels, cell proliferation and apoptotic cell death, neutrophil adhesion to the vessel wall, and vascular tone and in the development of cardiovascular diseases to name some important examples. Ceramide triggers the generation of ROS and increases oxidative stress in many mammalian cells and animal models. Moreover, inhibition of ROS generating enzymes or treatment of antioxidants impairs sphingomyelinase activation and ceramide production. Thus, a new concept has been proposed that ceramide-enriched raft platforms are important redox signaling platforms that amplify activation of ROS generating enzymes (e.g. NADPH oxidase family enzymes) and sphingomyelinases. The general function of ceramide to form redox signaling platforms amplifying oxdative stress might be critically involved in the dysfunction of vascular cells induced by death receptor ligands and stress stimuli contributing to the development of cardiovascular diseases.