The effect of insulin to decrease neointimal growth after arterial injury is endothelial nitric oxide synthase-dependent

Guo, Jing; Breen, Danna M.; Pereira, Troy J.; Dalvi, Prasad S.; Zhang, Hangjun; Mori, Yusaku; Ghanim, Husam; Tumiati, Laura C.; Fantus, I. George; Bendeck, Michelle P.; Dandona, Paresh; Rao, Vivek; Dolinsky, Vernon W.; Heximer, Scott P.; Giacca, Adria

doi:10.1016/j.atherosclerosis.2015.04.799

Cited by 22 publications

(34 citation statements)

References 45 publications

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“…Previous studies using genetically modified mice showed that eNOS (25,26) and nNOS (47) are protective against atherosclerosis while iNOS (9, 30) is detrimental. Insulin was found to decrease iNOS expression in VSMCs (6) and in our study in injured rat arteries (17). Similarly, in the present study, insulin decreased iNOS expression in the plaque, and this decrease was abolished by L-NAME.…”

Section: Discussionsupporting

confidence: 87%

“…Similarly, in the present study, insulin decreased iNOS expression in the plaque, and this decrease was abolished by L-NAME. Insulin is also known to increase eNOS transcription and activity in the endothelium (31), and we (17) have recently shown that the effect of insulin to decrease neointimal growth after arterial injury is mediated by eNOS. Our data suggest that insulin also increased phosphorylated eNOS and total nNOS expression in the plaque, although due to the low number of slides available for staining, significance was reached only with two-way ANOVA.…”

Section: Discussionmentioning

confidence: 91%

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Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice

Mori

Chiang

Bendeck

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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It has been argued whether insulin accelerates or prevents atherosclerosis. Although results from in vitro studies have been conflicting, recent in vivo mice studies demonstrated antiatherogenic effects of insulin. Insulin is a known activator of endothelial nitric oxide synthase (NOS), leading to increased production of NO, which has potent antiatherogenic effects. We aimed to examine the role of NOS in the protective effects of insulin against atherosclerosis. Male apolipoprotein E-null mice (8 wk old) fed a high-cholesterol diet (1.25% cholesterol) were assigned to the following 12-wk treatments: control, insulin (0.05 U/day via subcutaneous pellet), N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME, via drinking water at 100 mg/l), and insulin plus l-NAME. Insulin reduced atherosclerotic plaque burden in the descending aorta by 42% compared with control (plaque area/aorta lumen area: control, 16.5 ± 1.9%; insulin, 9.6 ± 1.3%, P < 0.05). Although insulin did not decrease plaque burden in the aortic sinus, macrophage accumulation in the plaque was decreased by insulin. Furthermore, insulin increased smooth muscle actin and collagen content and decreased plaque necrosis, consistent with increased plaque stability. In addition, insulin treatment increased plasma NO levels, decreased inducible NOS staining, and tended to increase phosphorylated vasodilator-stimulated phosphoprotein staining in the plaques of the aortic sinus. All these effects of insulin were abolished by coadministration of l-NAME, whereas l-NAME alone showed no effect. Insulin also tended to increase phosphorylated endothelial NOS and total neuronal NOS staining, effects not modified by l-NAME. In conclusion, we demonstrate that insulin treatment decreases atherosclerotic plaque burden and increases plaque stability through NOS-dependent mechanisms.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 91%

Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice

Mori

Chiang

Bendeck

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Firstly, insulin is a nitric oxide (NO)-dependent vasodilator32 and endothelial insulin-mediated vasodilatation has been shown to be mediated by endothelial nitric oxide synthase (eNOS)33. Human studies and animal models strongly link insulin resistance with decreased NO bioavailability: In humans, NO-mediated insulin-induced vasodilatation is impaired in insulin-resistant states34; and NO bioavailability is known to be reduced both in animal models of obesity and diabetes35 and in obese and diabetic humans36.…”

Section: Discussionmentioning

confidence: 99%

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Fernandez‐Twinn

Gascoin

Musiał

et al. 2017

Sci Rep

109

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The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

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“…PI3K/Akt phosphorylation increases cell proliferation [19], and it is upstream of eNOS [20]. We tested Akt phosphorylation by western blotting.…”

Section: Resultsmentioning

confidence: 99%

“…Co-treatment of nicorandil increased eNOS mRNA expression. Akt phosphorylation is upstream of eNOS and increases endothelial cells proliferation [20]. Rapamycin inhibits cell proliferation and Akt phosphorylation in endothelial cells [28].…”

Section: Discussionmentioning

confidence: 99%

Delayed reendothelialization with rapamycin is rescued by the addition of nicorandil in balloon-injured rat carotid arteries

et al. 2016

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Rapamycin is an immunosuppressive agent that is added to drug eluting stents. It prevents restenosis, but it also impairs reendothelialization. Nicorandil is a hybrid agent with adenosine triphosphated (ATP)-sensitive K+ (KATP) channel opener and nitrate properties. It prevents oxidative stress and cell apoptosis induced by rapamycin in endothelial cells in vitro. However, whether nicorandil promotes reendothelialization after angioplasty delayed by rapamycin remains to be determined. Balloon injury model was established in SD rats. Nicorandil increased reendothelialization impaired by rapamycin, and it decreased xanthine oxidase (XO)-generated reactive oxygen species (ROS) induced by rapamycin. In addition, eNOS expression inhibited by rapamycin was increased by nicorandil in vivo. In vitro, rapamycin-impeded cardiac microvascular endothelial cells (CMECs) migration, proliferation and rapamycin-induced ROS production were reversed by nicorandil. Knockdown of XO partially inhibited rapamycin-induced ROS production and cell apoptosis in CMECs, and it promoted CMECs migration and proliferation suppressed by rapamycin. Knockdown of Akt partially prevents eNOS upregulation promoted by nicorandil. The beneficial effect of nicorandil is exhibited by inhibiting XO and up-regulating Akt pathway. Nicorandil combined with rapamycin in effect rescue the deficiencies of rapamycin alone in arterial healing after angioplasty.

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The effect of insulin to decrease neointimal growth after arterial injury is endothelial nitric oxide synthase-dependent

Cited by 22 publications

References 45 publications

Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice

Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

Delayed reendothelialization with rapamycin is rescued by the addition of nicorandil in balloon-injured rat carotid arteries

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