1. Reduced NO-cGMP Signaling Contributes to Vascular Inflammation and Insulin Resistance Induced by High-Fat Feeding
- Author
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Priya Handa, Hunter Wessells, Norma O. Rizzo, Sanshiro Tateya, Guenter Daum, Matilda Pham, Michael W. Schwartz, Ian Luttrell, Francis Kim, and Ezekiel Maloney
- Subjects
Male ,Phosphodiesterase Inhibitors ,medicine.medical_treatment ,Palmitic Acid ,Aorta, Thoracic ,Piperazines ,Mice ,Phosphatidylinositol 3-Kinases ,Insulin ,Sulfones ,Enzyme Inhibitors ,Phosphorylation ,Cyclic GMP ,Cells, Cultured ,Mice, Knockout ,NF-kappa B ,Intercellular adhesion molecule ,I-kappa B Kinase ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Insulin Receptor Substrate Proteins ,Aortic Diseases ,Down-Regulation ,Inflammation ,Biology ,Nitric Oxide ,Article ,Sildenafil Citrate ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,Nitric Oxide Donors ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Endothelial Cells ,Phosphodiesterase 5 Inhibitors ,medicine.disease ,Dietary Fats ,Mice, Inbred C57BL ,Disease Models, Animal ,Insulin receptor ,Endocrinology ,Purines ,biology.protein ,Insulin Resistance ,Soluble guanylyl cyclase ,Cell Adhesion Molecules ,Proto-Oncogene Proteins c-akt - Abstract
Objective— Diet-induced obesity (DIO) in mice causes vascular inflammation and insulin resistance that are accompanied by decreased endothelial-derived NO production. We sought to determine whether reduced NO-cGMP signaling contributes to the deleterious effects of DIO on the vasculature and, if so, whether these effects can be blocked by increased vascular NO-cGMP signaling. Methods and Results— By using an established endothelial cell culture model of insulin resistance, exposure to palmitate, 100 μmol/L, for 3 hours induced both cellular inflammation (activation of IKKβ–nuclear factor-κB) and impaired insulin signaling via the insulin receptor substrate–phosphatidylinositol 3-kinase pathway. Sensitivity to palmitate-induced endothelial inflammation and insulin resistance was increased when NO signaling was reduced using an endothelial NO synthase inhibitor, whereas endothelial responses to palmitate were blocked by pretreatment with either an NO donor or a cGMP analogue. To investigate whether endogenous NO-cGMP signaling protects against vascular responses to nutrient excess in vivo, adult male mice lacking endothelial NO synthase were studied. As predicted, both vascular inflammation (phosphorylated IκBα and intercellular adhesion molecule levels) and insulin resistance (phosphorylated Akt [pAkt] and phosphorylated eNOS [peNOS] levels) were increased in endothelial NO synthase −/− (eNOS −/− ) mice, reminiscent of the effect of DIO in wild-type controls. Next, we asked whether the vascular response to DIO in wild-type mice can be reversed by a pharmacological increase of cGMP signaling. C57BL6 mice were either fed a high-fat diet or remained on a low-fat diet for 8 weeks. During the final 2 weeks of the study, mice on each diet received either placebo or the phosphodiesterase-5 inhibitor sildenafil, 10 mg/kg per day orally. In high-fat diet–fed mice, vascular inflammation and insulin resistance were completely prevented by sildenafil administration at a dose that had no effect in mice fed the low-fat diet. Conclusion— Reduced signaling via the NO-cGMP pathway is a mediator of vascular inflammation and insulin resistance during overnutrition induced by high-fat feeding. Therefore, phosphodiesterase-5, soluble guanylyl cyclase, and other molecules in the NO-cGMP pathway (eg, protein kinase G) constitute potential targets for the treatment of vascular dysfunction in the setting of obesity.
- Published
- 2010