Electrophoretic studies on the phosphorylation of stathmin and mitogen-activated protein kinases in neuronal cell death induced by oxidized very-low-density lipoprotein with apolipoprotein E.
In the central nervous system, stressful conditions can easily cause the oxidation of lipoprotein particles, followed by the oxidative modification of apolipoproteins such as apolipoprotein E (apoE) and the production of free radicals and aldehydes. We have confirmed that oxidized very-low-density lipoprotein (VLDL) inhibits the proliferation, viability and differentiation of neuronal PC12 cells leading to cell death. The cells internalized intact apoE, but did not internalize oxidized apoE. The phosphorylation of stathmin and various mitogen-activated protein (MAP) kinases including extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was examined in PC12 cells exposed to native and oxidized VLDL, H(2)O(2) (which generates free radicals), and 4-hydroxy-2-nonenal (HNE) (an aldehyde). Oxidized VLDL and H(2)O(2) reduced stathmin phosphorylation while HNE increased it, suggesting that oxidized VLDL and H(2)O(2) stimulated similar signal transduction pathways. Based on the results, free radicals, but not aldehydes may play a major role in the neuronal cell death induced by lipoprotein oxidation. Furthermore, the phosphorylation status of MAP kinases indicated that the activation of the JNK cascade might be required for neuronal cell death.
Yamashita
Hiroshi
H
Department of Neurology and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
Nakamura
Kazuyuki
K
Arai
Hirofumi
H
Furumoto
Hiroko
H
Fujimoto
Masanori
M
Kashiwagi
Shiro
S
Morimatsu
Mitsunori
M
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008868:Microtubule Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D016716:PC12 Cells; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D050777:Stathmin
D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D008868:Microtubule Proteins; D010750:Phosphoproteins; D050777:Stathmin; C108132:oxidized very low density lipoprotein; D020928:Mitogen-Activated Protein Kinases