5-Lipoxygenase is involved in the angiotensin II-induced NAD(P)H-oxidase activation.
Angiotensin II (ANG II)-induced interleukin (IL)-6 synthesis requires NAD(P)H-oxidase-derived superoxide anions. Since NAD(P)H-oxidase activation by cytokines involves 5-lipoxygenase (LOX)-derived leukotriene B(4) (LTB(4)) formation, we postulated that LTB(4) is involved in the ANG II-dependent NAD(P)H-oxidase activation. Therefore, 5-LOX expression and LTB(4) formation following ANG II (100nM) stimulation were determined in rat aortic smooth muscle cells (SMC). Reactive oxygen species (ROS)-formation and IL-6 mRNA expression were analyzed following ANG II and LTB(4) (0.6 microM) stimulation. 5-LOX mRNA and protein were detected in SMC. ANG II-induced LTB(4) formation at 2.5min and was followed by an increase in ROS-formation and IL-6 mRNA expression. Blockade of 5-LOX by MK886 (200nM) abrogated LTB(4)-formation, ROS-formation, and IL-6 mRNA expression. Moreover, LTB(4)-induced ROS-formation and IL-6 mRNA expression was abolished by NAD(P)H-oxidase inhibition using diphenyleneiodonium chloride (DPI 10 microM). In conclusion, the present study demonstrates that ANG II enhances LTB(4)-formation in an 5-LOX dependent manner. LTB(4) activates the vascular type NAD(P)H-oxidase, leading to an increase in IL-6 transcripts.
Luchtefeld
Maren
M
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Drexler
Helmut
H
Schieffer
Bernhard
B
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D002722:Chlorobenzenes
D000804:Angiotensin II; D001094:Arachidonate 5-Lipoxygenase; D007211:Indoles; D015850:Interleukin-6; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; C060893:MK-886; D002722:Chlorobenzenes