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Heterozygous eNOS deficiency is associated with oxidative stress and endothelial dysfunction in diet-induced obesity
- Source :
- Physiological Reports
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
Abstract
- Heterozygous endothelial nitric oxide synthase (eNOS) deficiency is associated with normal endothelium‐dependent responses, however, little is known regarding the mechanisms that maintain or impair endothelial function with heterozygous eNOS deficiency. The goals of this study were to (1) determine mechanism(s) which serve to maintain normal endothelial function in the absence of a single eNOS gene; and (2) to determine whether heterozygous eNOS deficiency predisposes blood vessels to endothelial dysfunction in response to a high‐fat diet (HFD). Responses of carotid arteries were examined in wild‐type ( eNOS +/+ ) and heterozygous eNOS‐deficient ( eNOS +/− ) treated with either vehicle (saline), NG‐nitro‐L‐arginine (L‐NNA, 100 μmol/L), an inhibitor of nitric oxide synthase, or 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 1 μmol/L), an inhibitor of soluble guanylyl cyclase (sGC), and in eNOS +/+ and eNOS +/− mice fed a control (10%) or a 45% HFD (kcal from fat). Responses to acetylcholine (ACh) were similar in vehicle‐treated arteries from eNOS +/+ and eNOS +/− mice, and were equally inhibited by L‐NNA and ODQ. Phosphorylation of eNOS Ser1176, a site associated with increased eNOS activity, was significantly greater in eNOS +/− mice most likely as a compensatory response for the loss of a single eNOS gene. In contrast, responses to ACh were markedly impaired in carotid arteries from eNOS +/− , but not eNOS +/+ , mice fed a HFD. Vascular superoxide levels as well as plasma levels of the pro‐inflammatory cytokine interleukin‐6 (IL‐6) were selectively increased in HFD‐fed eNOS +/− mice. In reconstitution experiments, IL‐6 produced concentration‐dependent impairment of endothelial responses as well as greater increases in NADPH‐stimulated superoxide levels in arteries from eNOS +/− mice fed a control diet compared to eNOS +/+ mice. Our findings of increased Ser1176‐phosphorylation reveal a mechanism by which NOS‐ and sGC‐dependent endothelial function can be maintained with heterozygous eNOS deficiency. In addition, heterozygous eNOS deficiency predisposes blood vessels to developing endothelial dysfunction in response to a HFD. The impairment produced by a HFD in eNOS +/− mice appears to be mediated by IL‐6‐induced increases in vascular superoxide. These findings serve as an important example of eNOS haploinsufficiency, one that may contribute to the development of carotid artery disease in obese humans.
- Subjects :
- Cardiovascular Conditions, Disorders and Treatments
medicine.medical_specialty
Physiology
medicine.medical_treatment
030204 cardiovascular system & hematology
medicine.disease_cause
Signalling Pathways
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Enos
Physiology (medical)
Internal medicine
medicine
genetically altered mice
Endothelial dysfunction
Nutrition
Original Research
030304 developmental biology
0303 health sciences
Carotid artery disease
biology
business.industry
Superoxide
high fat diet
medicine.disease
biology.organism_classification
haploinsufficiency
Nitric oxide synthase
Cytokine
Endocrinology
diabetes mellitus, type 2
chemistry
Interleukin‐6
biology.protein
NOS3
Soluble guanylyl cyclase
business
Adipose Tissue and Obesity
Oxidative stress
Acetylcholine
medicine.drug
Subjects
Details
- ISSN :
- 2051817X
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Physiological Reports
- Accession number :
- edsair.doi.dedup.....6a2fe2e059a50a99a9cb2bfa6349acd4