Interleukin-6 Impairs the Insulin Signaling Pathway, Promoting Production of Nitric Oxide in Human Umbilical Vein Endothelial Cells

Andreozzi, Francesco; Laratta, Emanuela; Procopio, Cristina; Hribal, Marta Letizia; Sciacqua, Angela; Perticone, Maria; Miele, Claudia; Perticone, Francesco; Sesti, Giorgio

doi:10.1128/mcb.01340-06

Cited by 104 publications

(84 citation statements)

References 41 publications

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“…23 Recent reports suggest that there is crosstalk between the eNOS and MAP kinase pathways. Andreozzi et al 24 reported that interleukin-6 impairs the vasodilator effects of insulin that are mediated by the eNOS pathway in endothelial cells through activation of JNK and ERK. These reports prompted us to examine whether apoCIII also would activate MAP kinase in HUVECs through its involvement in the eNOS pathway.…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

et al. 2008

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Background-Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-␤ (PKC␤). Because PKC␤ impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo. Methods and Results-ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKC␤ in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKC␤. The impaired insulin signaling was restored by PKC␤ inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKC␤ inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKC␤, which inhibits the IRS-1/PI3K/Akt/eNOS pathway. Conclusion-Our

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Section: Discussionmentioning

confidence: 99%

“…A PKC␤-specific inhibitor partially reversed apoCIII-induced ERK activation ( Figure 4B). Andreozzi et al 24 reported that endothelial dysfunction is mediated through activation of JNK or ERK. Recent studies reported that ERK and PKC isoforms induce Ser 616 phosphorylation of IRS-1.…”

Section: Apociii Activates Map Kinase In Huvecsmentioning

confidence: 99%

Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

et al. 2008

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“…Waist circumference was the strongest risk factor associated with IMT in a stepwise multivariate regression analysis. It is likely that free fatty acids and adipokines such as tumor necrosis factor-␣ and interleukin-6, which are predominantly secreted from visceral fat and affect vasculature (27)(28)(29)(30), may be responsible for the strong relationship between central obesity and early atherosclerosis. Interestingly, we found that plasma IGF-1 levels were independently associated with carotid IMT, suggesting that low IGF-1 levels could contribute to early atherosclerosis observed in IRO and MHO women compared with nonobese women.…”

Section: Research Design and Methods -mentioning

confidence: 99%

Metabolically Healthy but Obese Women Have an Intermediate Cardiovascular Risk Profile Between Healthy Nonobese Women and Obese Insulin-Resistant Women

Marini¹,

Succurro

Frontoni³

et al. 2007

Diabetes Care

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140

117

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O besity is associated with metabolic and cardiovascular risk factors that include type 2 diabetes, hypertension, and dyslipidemia (1-4). A subset of obese subjects has been identified that appears to be protected from obesity-related metabolic abnormalities (5-11). These subjects, termed metabolically healthy but obese (MHO), are relatively insulin sensitive and have a rather favorable cardiovascular risk profile (5-11). Although the existence of MHO individuals has been recognized, only a few studies have examined in detail the metabolic characteristics associated with their protective profile (5-13). Whereas MHO individuals appear to have a more favorable cardiovascular risk profile than insulinresistant obese (IRO) individuals, they show early signs of atherosclerosis compared with lean subjects, which could not be explained by alterations in cardiovascular risk factors (12). Among the factors that may account for the early atherosclerosis, insulin-like growth factor (IGF)-1 is a plausible candidate because low plasma IGF-1 concentrations are associated with type 2 diabetes, insulin resistance (14 -16), and increased risk of coronary artery disease (17)(18)(19)(20)(21)(22). To further characterize the protective profile of MHO individuals, we compared clinical characteristics, including cardiovascular risk factors, plasma IGF-1 levels, and intima-media thickness (IMT) of the common carotid artery, of a group of MHO women from a cohort of nondiabetic Italian Caucasians with those of two age-matched groups comprising healthy nonobese or IRO women. RESEARCH DESIGN AND METHODS -The study group consisted of 73 nonobese (BMI Ͻ27 kg/m 2 ) and 80 obese (BMI Ͼ30 kg/m 2 ) women, recruited by announcements in the Universities of Rome and Catanzaro areas. The inclusion criteria included the following: aged 19 -48 years, absence of diabetes, and absence of known inflammatory disease or pathologies affecting glucose metabolism. A total of 68 women in the cohort used oral contraceptives, whereas the remaining had regular menses. Subjects underwent anthropometrical evaluation, a 75-g oral glucose tolerance test, and a euglycemic-hyperinsulinemic clamp, as previously described (23). Glucose disposal (M) was calculated as the mean rate of glucose infusion during the last 60 min of the examination and was expressed as milligrams per minute per kilogram fatfree mass (M FFM ). IMT of the common carotid artery was measured by highresolution B-mode ultrasound using an ATL-HDI 3000 system equipped with a 5-MHz linear array transducer, as previously described (24). The protocol was approved by the ethics committees, and informed written consent was obtained from all participants. The investigations were performed in accordance with the principles of the Declaration of Helsinki. Plasma insulin and IGF-1 concentrations were determined by a chemiluminescence-based assay. Relationships between variables were sought by stepwise multivariate linear regression analysis. RESULTS -Because insulin sensitivity is a continuous trait, there is n...

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“…In cultured endothelial cells, impaired insulin-stimulated PI3K/Akt/NO synthesis has been reported in response to free fatty acids and pro-inflammatory signals including angiotensin II, TNFα and IL6 [25,68,69,70,71].…”

Section: Does Vascular Insulin Resistance Contribute To the Cardiovasmentioning

confidence: 99%

Examining the Role of Insulin in the Regulation of Cardiovascular Health

Salt

2012

Future Cardiol.

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Examining the role of insulin in the regulation of cardiovascular health SUMMARYA substantial body of evidence has reported insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood.Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed.

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Interleukin-6 Impairs the Insulin Signaling Pathway, Promoting Production of Nitric Oxide in Human Umbilical Vein Endothelial Cells

Cited by 104 publications

References 41 publications

Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

Metabolically Healthy but Obese Women Have an Intermediate Cardiovascular Risk Profile Between Healthy Nonobese Women and Obese Insulin-Resistant Women

Examining the Role of Insulin in the Regulation of Cardiovascular Health

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