Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.
Angiotensin II type 1 (AT1) receptor activation as well as proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the development and progression of atherosclerosis. The detailed underlying mechanisms including interactions between inflammatory agonists and the renin-angiotensin system are poorly understood. Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments. Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT1 receptor mRNA de novo synthesis but not mRNA stability. Preincubation of VSMCs with IL-6 resulted in an enhanced angiotensin II-induced production of reactive oxygen species, as assessed by DCF fluorescence laser microscopy. Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation. These effects were completely omitted in AT1 receptor knockout mice (AT1A-/- mice). Upregulation of vascular AT1 receptor expression in vitro and in vivo is decisively involved in IL-6-induced propagation of oxidative stress and endothelial dysfunction. This interaction of the proinflammatory cytokine IL-6 with the renin-angiotensin system may represent an important pathogenetic mechanism in the atherosclerotic process.
Wassmann
Sven
S
Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany. wassmann@med-in.uni-saarland.de
Stumpf
Michaela
M
Strehlow
Kerstin
K
Schmid
Andreas
A
Schieffer
Bernhard
B
Böhm
Michael
M
Nickenig
Georg
G
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology; D003433:Crosses, Genetic; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000150:complications; D015850:Interleukin-6 / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
D015850:Interleukin-6; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D011994:Recombinant Proteins