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eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice

Please always quote using this URN: urn:nbn:de:bvb:20-opus-134866
  • 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) andBackground: 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.show moreshow less

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Metadaten
Author: Padmapriya Ponnuswamy, Angelika Schröttle, Eva Ostermeier, Sabine Grüner, Paul L. Huang, Georg Ertl, Ulrich Hoffmann, Bernhard Nieswandt, Peter J. Kuhlencordt
URN:urn:nbn:de:bvb:20-opus-134866
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik I
Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):PLoS One
Year of Completion:2012
Volume:7
Issue:1
Pagenumber:e30193
Source:PLoS ONE 7(1): e30193. doi:10.1371/journal.pone.0030193
DOI:https://doi.org/10.1371/journal.pone.0030193
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:accelerated atherosclerosis; apolipoprotein E; deficient mice; double knockout mice; endothelial cell interactions; in vivo; lesion formation; leukocyte adhesion; nitric oxide synthase; platelet adhesion
Release Date:2017/12/17
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung