Published online before print December 29, 2003, doi: 10.1161/01.RES.0000115557.25127.8D
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Submitted on September 26, 2003
Revised on November 20, 2003
Accepted on December 5, 2003
Interleukin-6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor
Sven Wassmann *;
From the Medizinische Klinik und Poliklinik (S.W., M.S., K.S., M.B., G.N.), Innere Medizin III, and Physiologisches Institut (A.S.), Universitätskliniken des Saarlandes, Homburg/Saar, Germany; and Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Hannover, Germany.
* To whom correspondence should be addressed. E-mail: wassmann{at}med-in.uni-saarland.de.
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.
Key words: endothelial dysfunction • AT1 receptor • interleukin-6 • inflammation • oxidative stress
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