Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.

Abstract

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.

• Authors: Sven Wassmann, Michaela Stumpf, Kerstin Strehlow, Andreas Schmid, Bernhard Schieffer, Michael Böhm, Georg Nickenig
• Journal: Circulation research (Circ Res) Vol. 94 Issue 4 Pg. 534-41 (Mar 05 2004) ISSN: 1524-4571 [Electronic] United States
• PMID: 14699015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Reactive Oxygen Species
• Receptor, Angiotensin, Type 1
• Recombinant Proteins

Topics

• Animals
• Aortic Diseases (etiology, pathology)
• Arteriosclerosis (etiology, pathology)
• Crosses, Genetic
• Endothelium, Vascular (drug effects, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Inflammation (complications)
• Interleukin-6 (pharmacology, toxicity)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Rats
• Reactive Oxygen Species (metabolism)
• Receptor, Angiotensin, Type 1 (biosynthesis, deficiency, genetics)
• Recombinant Proteins (pharmacology, toxicity)
• Renin-Angiotensin System (drug effects, physiology)