A novel antioxidant, octyl caffeate, suppression of LPS/IFN-gamma-induced inducible nitric oxide synthase gene expression in rat aortic smooth muscle cells.
In the present study, we investigated the effects and mechanisms of a novel potent antioxidant, octyl caffeate, on the induction of iNOS expression by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in cultured primary rat aortic smooth muscle cells (RASMCs) in vitro and LPS-induced hypotension in vivo. Octyl caffeate (0.1-1.0 microM) exerted a concentration-dependent inhibition of iron-catalyzed lipid peroxidation in rat brain homogenates. Furthermore, octyl caffeate (20, 50, and 100 microM) concentration-dependently diminished the initial rate of superoxide-induced NBT reduction and the enzymatic activity of xanthine oxidase. It also concentration-dependently (1-50 microM) inhibited the NO production, iNOS protein and messenger RNA expressions upon stimulation by LPS (100 microg/mL)/IFN-gamma (100U/mL) in RASMCs. In addition, we found that octyl caffeate did not significantly affect IkappaBalpha degradation stimulated by LPS/IFN-gamma in RASMCs. On the other hand, octyl caffeate (10 and 50 microM) significantly suppressed activation of c-Jun-N-terminal kinase and extracellular signal-regulated kinase. Moreover, octyl caffeate (10mg/kg, i.v.) significantly inhibited the fall in mean arterial pressure stimulated by LPS (7.5mg/kg) in rats. In conclusion, we demonstrate that a novel potent antioxidant, octyl caffeate, significantly ameliorates circulatory failure of endotoxemia in vivo by a mechanism involving suppression of iNOS expression through inactivation of mitogen-activated protein kinases in RASMCs.
Hsiao
George
G
Graduate Institute of Medical Sciences and Department of Pharmacology, Taipei Medical University, 250 Wu-Shing Street, Taiwan, ROC.
Shen
Ming-Yi
MY
Chang
Wen-Chiung
WC
Cheng
Yu-Wen
YW
Pan
Shiow-Lin
SL
Kuo
Yueh-Hsiung
YH
Chen
Tzeng-Fu
TF
Sheu
Joen-Rong
JR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta; D002109:Caffeic Acids / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D002109:Caffeic Acids; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C474929:octyl caffeate; D013481:Superoxides; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C040048:caffeic acid