Abstract 15156: Ablation of LysM+ Inflammatory Monocytes Reduces Uncopling of Endotheial NO Synthase and iNOS Derived Nitrosative Stress in Angiotensin Ii Induced Vascular Dysfunction
Background: Endothelial nitric oxide synthase (eNOS) uncoupling occurs in disease states of vascular dysfunction and amplifies vascular oxidative stress and loss of NO bioactivity. Inflammatory myelomonocytic cells as a major source of superoxide are critical for angiotensin II induced vascular dysfunction; however their role in mediating eNOS uncopuling has not been defined yet.
Methods and results: Angiotensin II (1mg/kg/d, 7d) infusion led to infiltration of CD11b+Gr-1lowiNOS+ monocytes and macrophages into mouse aorta (revealed by FACS analysis). In parallel ATII increased vascular nox4 and heme oxygenase 1 expression (assessed by Western blot analysis) and induced eNOS uncoupling, measured by differential NOS dependent superoxide formation in the endothelial layer and glutathionylation of eNOS. Toxin mediated ablation of macrophages in LysMiDTR transgenic mice restored all of these parameters. Conversely, ablation of LysM+ cells reduced iNOS expression and normalized vascular levels of tetrahydrobiopterin (measured by high-performance liquid chromatography) and expression of the GTP cyclohydrolase-1, essential for tetrahydrobiopterin synthesis, all of which were increased by angiotensin II in control mice.
Conclusion: Depletion of LysM+ monocytes reduces angiotensin II induced eNOS uncopuling in vascular dysfunction, and simultaneously protects from iNOS mediated nitrosative stress: These findings highlight the role of vascular inflammatory cells in disturbed NO-bioactivity and vascular function
- © 2013 by American Heart Association, Inc.