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Decreased production of neuronal NOS‐derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis
Author(s) -
Capettini LSA,
Cortes SF,
Silva JF,
AlvarezLeite JI,
Lemos VS
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01500.x
Subject(s) - endothelial dysfunction , enos , endocrinology , medicine , vasodilation , endothelium , apolipoprotein e , chemistry , myograph , endothelial stem cell , nitric oxide synthase , biology , nitric oxide , biochemistry , in vitro , disease
BACKGROUND AND PURPOSE Reduced NO availability has been described as a key mechanism responsible for endothelial dysfunction in atherosclerosis. We previously reported that neuronal NOS (nNOS)‐derived H 2 O 2 is an important endothelium‐derived relaxant factor in the mouse aorta. The role of H 2 O 2 and nNOS in endothelial dysfunction in atherosclerosis remains undetermined. We hypothesized that a decrease in nNOS‐derived H 2 O 2 contributes to the impaired vasodilatation in apolipoprotein E‐deficient mice (ApoE −/− ). EXPERIMENTAL APPROACH Changes in isometric tension were recorded on a myograph; simultaneously, NO and H 2 O 2 were measured using carbon microsensors. Antisense oligodeoxynucleotides were used to knockdown eNOS and nNOS in vivo . Western blot and confocal microscopy were used to analyse the expression and localization of NOS isoforms. KEY RESULTS Aortas from ApoE −/− mice showed impaired vasodilatation paralleled by decreased NO and H 2 O 2 production. Inhibition of nNOS with L‐Arg NO2 ‐L‐Dbu, knockdown of nNOS and catalase, which decomposes H 2 O 2 into oxygen and water, decreased ACh‐induced relaxation by half, produced a small diminution of NO production and abolished H 2 O 2 in wild‐type animals, but had no effect in ApoE −/− mice. Confocal microscopy showed increased nNOS immunostaining in endothelial cells of ApoE −/− mice. However, ACh stimulation of vessels resulted in less phosphorylation on Ser852 in ApoE −/− mice. CONCLUSIONS AND IMPLICATIONS Our data show that endothelial nNOS‐derived H 2 O 2 production is impaired and contributes to endothelial dysfunction in ApoE −/− aorta. The present study provides a new mechanism for endothelial dysfunction in atherosclerosis and may represent a novel target to elaborate the therapeutic strategy for vascular atherosclerosis.