Activation mechanisms of endothelial NF-kappaB, IKK, and MAP kinase by tert-butyl hydroperoxide.
Lipid peroxidation plays a major role in vascular dysfunction and age-related cardiovascular diseases. A major product of lipid peroxidation, tert-butyl hydroperoxide (t-BHP), has been reported to modulate vascular reactivity and cellular signaling. To better understand vascular abnormality, we set out to delineate the activation mechanism of nuclear factor kappa B (NF-kappaB) by t-BHP and the regulation of MAPK in endothelial cells. The results showed that t-BHP induces NF-kappaB activation by an inhibitor of kappaB (IkappaB) phosphorylation through IkappaB kinase (IKK) activation. Our data from this t-BHP study also showed increased p38 MAP kinase and ERK activity; however, interestingly, t-BHP showed no influence on JNK. Pretreatment with the p38 MAP kinase inhibitor, SB203580 and the ERK1/2 inhibitor, PD98059, prevented t-BHP-induced increases in p65 translocation, NF-kappaB luciferase activity, and phospho-IKKalpha/beta. Data suggested that t-BHP induces NF-kappaB activation through the IKK pathway, which involves p38 MAPK and ERK activation. This study illustrates a role of t-BHP in NF-kappaB activation and MAPK related-signaling pathways. The t-BHP-induced activation of NF-kappaB and MAPK could be a major player in vascular dysfunctions, as seen in oxidative stressed responses and the vascular inflammatory process.
Lee
Ji Young
JY
Genetic Engineering Research Institute, Aging Tissue Bank, Pusan National University, Busan 609-735, North Korea.
Yu
Byung Pal
BP
Chung
Hae Young
HY
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051550:I-kappa B Kinase; D008297:Male; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D020122:tert-Butylhydroperoxide / Q000378:metabolism
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D020122:tert-Butylhydroperoxide; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases