Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells

Interaction of oxidized low-density lipoprotein (LDL) with arterial smooth muscle cells (SMC) is believed to play a key role in the development of atherosclerosis. Depending on the extent of oxidation, apolipoproteins and/or lipids in the particle may be modified and thus lead to different cellular responses (e.g. proliferation or cell death). Here we report on the signaling effects of LDL, in which only the lipids were oxidized. This so-called minimally modified LDL (mmLDL) mainly activated components involved in stress response and apoptotic cell death including p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) as well as neutral and acid sphingomyelinase. In contrast, proliferative signaling elements such as extracellular regulated kinase, AKT-kinase and phospho-BAD seem to play a minor role as they were only slightly stimulated by mmLDL. Ceramide, the hydrolysis product of sphingomyelin, seems to be a key mediator as it mimics mmLDL by inducing activation of the same signaling components. Moreover, mmLDL- and ceramide-associated effects on apoptotic protein kinases were abolished by NB6, a specific inhibitor of acid sphingomyelinase. Thus, acid sphingomyelinase is very likely to be primarily responsible for triggering intracellular signal transduction in SMC after exposure to mmLDL via formation of ceramide by an autocatalytic mechanism.