eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE−/− Mice
Open Access
- 23 January 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (1), e30193
- https://doi.org/10.1371/journal.pone.0030193
Abstract
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. 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. 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.Keywords
This publication has 46 references indexed in Scilit:
- Oxidative Stress and Compartment of Gene Expression Determine Proatherosclerotic Effects of Inducible Nitric Oxide SynthaseThe American Journal of Pathology, 2009
- Improvement of vascular function by acute and chronic treatment with the PDE‐5 inhibitor sildenafil in experimental diabetes mellitusBritish Journal of Pharmacology, 2008
- Atheroprotective Effects of Neuronal Nitric Oxide Synthase in Apolipoprotein E Knockout MiceArteriosclerosis, Thrombosis, and Vascular Biology, 2006
- Nox1 Overexpression Potentiates Angiotensin II-Induced Hypertension and Vascular Smooth Muscle Hypertrophy in Transgenic MiceCirculation, 2005
- Role of endothelial nitric oxide synthase in endothelial activation: insights from eNOS knockout endothelial cellsAmerican Journal of Physiology-Cell Physiology, 2004
- A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion FormationThe Journal of Experimental Medicine, 2002
- Spin Trapping of Vascular Nitric Oxide Using Colloid Fe(II)-DiethyldithiocarbamateBiochemical and Biophysical Research Communications, 2000
- Enhanced atherosclerosis and kidney dysfunction in eNOS–/–Apoe–/– mice are ameliorated by enalapril treatmentJCI Insight, 2000
- The pathogenesis of atherosclerosis: a perspective for the 1990sNature, 1993
- The Reaction of no With SuperoxideFree Radical Research Communications, 1993