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.
Department of Biochemistry, Graz University of Technology, Petersgasse 12/2, A-8010, Austria.
Alexandra
A
Loidl
Ralf
R
Claus
Elisabeth
E
Ingolic
Hans-Peter
HP
Deigner
Albin
A
Hermetter
D017209:Apoptosis; D001161:Arteriosclerosis / Q000378:metabolism; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002384:Catalysis; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002518:Ceramides / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013997:Time Factors; D051025:bcl-Associated Death Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C494819:BAD protein, human; D002227:Carbazoles; D002352:Carrier Proteins; D002518:Ceramides; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C493192:N,N,N-(3-carbazolylpropyl)-(p-methoxyphenylethyl)methylamine; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D010100:Oxygen