eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice
| Autor: | Peter J. Kuhlencordt, Bernhard Nieswandt, Padmapriya Ponnuswamy, Paul L. Huang, Eva Ostermeier, Sabine Grüner, Ulrich Hoffmann, Angelika Schröttle, Georg Ertl |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Apolipoprotein E
medicine.medical_specialty Nitric Oxide Synthase Type III Endothelium lcsh:Medicine Cardiovascular Nitric Oxide Biochemistry Gene Expression Regulation Enzymologic Nitric oxide Mice chemistry.chemical_compound Model Organisms Apolipoproteins E Superoxides Enos Internal medicine Molecular Cell Biology medicine Animals ddc:610 lcsh:Science Biology Mice Knockout chemistry.chemical_classification Reactive oxygen species Multidisciplinary biology Superoxide lcsh:R Animal Models Atherosclerosis biology.organism_classification Mice Inbred C57BL Nitric oxide synthase medicine.anatomical_structure Endocrinology chemistry Cytoprotection biology.protein Medicine Blood Vessels lcsh:Q Reactive Oxygen Species Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 1, p e30193 (2012) |
| Popis: | Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels. Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects. |
| Databáze: | OpenAIRE |
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