Azelnidipine, a newly developed long-acting calcium antagonist, inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endothelial cells through its anti-oxidative properties.
Interleukin-8 (IL-8), a member of CXC chemokine family, has been found to play an important role in the pathogenesis of atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha) is involved in the development and progression of atherosclerosis as well. In this study, we investigated whether and how azelnidipine, a newly developed long-acting calcium antagonist, could inhibit TNF-alpha-induced IL-8 expression in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly increased intracellular reactive oxygen species (ROS) generation in HUVEC, which was completely blocked by azelnidipine or apocynin, an inhibitor of NADPH oxidase. Azelnidipine also completely prevented TNF-alpha-induced increase in NADPH oxidase activity in HUVEC. Further, azelnidipine was found to significantly inhibit activator protein-1 (AP-1) promoter activity and IL-8 expression in TNF-alpha-exposed HUVEC. An inhibitor of AP-1, curcumin, or an anti-oxidant, N-acetylcysteine, also inhibited the TNF-alpha-induced IL-8 expression in HUVEC. These results demonstrated that azelnidipine inhibited TNF-alpha-induced IL-8 expression in HUVEC by blocking NADPH oxidase-mediated ROS generation and subsequent AP-1 activation. Our present study suggests that azelnidipine may play a protective role in the development and progression of atherosclerosis through its anti-oxidative properties.
Yamagishi
Sho-ichi
S
Department of Internal Medicine III, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp
Inagaki
Yosuke
Y
Nakamura
Kazuo
K
Imaizumi
Tsutomu
T
D017311:Amlodipine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000096:biosynthesis*; D011869:Radioligand Assay; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology; D014471:Umbilical Veins / Q000201:enzymology
D000975:Antioxidants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D017311:Amlodipine; D001383:Azetidinecarboxylic Acid; C061679:azelnidipine