Inflammatory Monocytes Determine Endothelial Nitric Oxide Synthase Uncoupling and Nitro-oxidative Stress Induced by Angiotensin II [Immunology]

August 25th, 2014 by Kossmann, S., Hu, H., Steven, S., Schonfelder, T., Fraccarollo, D., Mikhed, Y., Brahler, M., Knorr, M., Brandt, M., Karbach, S. H., Becker, C., Oelze, M., Bauersachs, J., Widder, J., Munzel, T., Daiber, A., Wenzel, P.

Endothelial nitric oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not been defined yet. Angiotensin II (ATII, 1mg/kg/d, 7d) increased Ly6Chigh and CD11b+/iNOShigh leukocytes and upregulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS dependent NO formation was increased, whereas eNOS dependent NO formation was decreased in aortas of ATII infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphteria toxin mediated ablation of lysozyme M positive (LysM+) monocytes in ATII-infused LysMiDTR transgenic mice prevented eNOS glutathionylation and eNOS derived L-NAME sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I (GTPCH) expression and biopterin synthesis in paralell, which was reduced in monocyte depleted LysMiDTR mice. Vascular tetrahydrobiopterin was increased by ATII infusion, but even higher in monocyte-depleted ATII infused mice, which was paralelled by a strong upregulation of dihydrofolate reductase expression. EPR spectroscopy revealed, that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII induced endothelial dysfunction. In summary, ATII induces an inflammatory cell dependent increase of iNOS, GTPCH, tetrahydrobiopterin, NO-formation and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM+ monocytes.
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