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

Angiotensin II type 1 ( AT(1)) 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 AT(1) 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 AT(1) 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 AT(1) 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 AT(1) receptor knockout mice ( AT1A(-/-) mice). Upregulation of vascular AT(1) 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.