High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration

Hamuro, Masao; Polan, Jodie; Natarajan, Mohan; Mohan, Sumathy

doi:10.1016/s0021-9150(01)00719-5

Cited by 97 publications

(60 citation statements)

References 26 publications

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“…Bovine aortic endothelial cells (BAECs, Clonetics, San Diego, CA) were cultured in MCDB-131 medium (Sigma, St. Louis, MO) containing 10% bovine calf serum (BCS, Hyclone, Kansas City, KS) and enriched with 250 ng/ml fibroblast growth factor (PeproTech, Rocky Hill, NJ), 20 ng/ml of epidermal growth factor (PeproTech), 1 g/ml of hydrocortisone (Sigma), 100 U/ml of penicillin, and 100 mg/ml streptomycin (Media-tech, Herndon, VA) (12,21). Cells from passages 4 to 7 were used in all the experiments.…”

Section: Methodsmentioning

confidence: 99%

High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction

Mohan¹,

Konopiński²,

Yan³

et al. 2009

American Journal of Physiology-Cell Physiology

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diabetes; endothelial nitric oxide synthase ACCELERATED ATHEROSCLEROSIS, one of the major vascular complications of diabetes, is attributed to hyperglycemia mediatedendothelial dysfunction (6). Endothelial dysfunction is characterized by the loss of nitric oxide (NO) bioactivity in the vessel wall with concomitant increase in superoxide release, which impairs vasodilatation, inhibits protection against leukocyteendothelial interactions, platelet aggregation, and adhesion and smooth muscle cell proliferation (3,17,31). The optimal generation of NO from endothelial nitric oxide synthase (eNOS) activity is dependent on several factors, including availability of the substrate L-arginine (9) and the cofactor tetrahydrobiopterin (BH4) (1). The activation of eNOS is a complex process and may be regulated by 1) both transcriptional and posttranslational mechanisms, 2) site-specific phosphorylation of eNOS, 3) protein-protein interactions, 4) prosthetic groups, and 5) calcium and calmodulin (8).eNOS has been shown to interact with several regulatory proteins such as heat shock protein-90 (Hsp-90), caveolin-1, G protein-coupled receptors, NO-interacting protein (NOSIP), Dynamin-2, and Porin (8). In endothelial cells, both BH 4 and Hsp-90 have been shown to be important effectors in regulating eNOS activity. Hsp-90 is known to regulate calciumdependent dissociation of eNOS from caveolin-1, enzyme activation, maturation, and trafficking, followed by the Aktdependent activation and phosphorylation of serine 1177 (human eNOS) or serine 1179 (bovine eNOS) (8). Phosphorylation of eNOS is a key posttranslational modification that was believed to be a key determinant of eNOS activity associated with NO generation. The binding of Hsp-90 to eNOS ensures the transition from the early Ca 2ϩ -dependent to the late phosphorylation-dependent activation of eNOS (18). Failure of this binding has been demonstrated to cause eNOS uncoupling and increased eNOS-dependent superoxide anion production (20,28,30).A recent study in the diabetes literature has demonstrated that chronic exposure of endothelial cells to high glucose (HG) conditions downregulate both protein interaction between eNOS and Hsp-90 and the recruitment of activated Akt. The end result is the deactivation of eNOS and imbalance in NO versus reactive oxygen species (ROS) levels (18). Evidence of metformin-stimulated NOS in vivo (5) by promoting the association of Hsp-90 further supports the results of an earlier study (18) and confirms the concept that elevated glucose downregulates the interaction of eNOS and Hsp-90.Parallel studies investigating NO production in endothelial cells under conditions of HG suggested that HG-mediated endothelial dysfunction involves activation of IKK␤, which inhibits insulin receptor substrate (IRS-1)/phosphatidylinositol 3-kinase (PI3 kinase) signaling and therefore attenuates NO production (14). This has been implicated in insulin resistance, a common complication of diabetes.Requirement of Hsp-90 for the activation of IKK complex consisting of ...

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Section: Methodsmentioning

confidence: 99%

High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction

Mohan¹,

Konopiński²,

Yan³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…11 To verify NO identification, migrating HAEC on both surfaces were preincubated with the specific NO synthase inhibitor L-NAME (0.5 mmol/L) as a negative control. 12 Expression of inflammatory markers TNF-α and VCAM-1 was detected using fluorescently tagged specific antibodies (Life Technologies).…”

Section: Ec Migration Studiesmentioning

confidence: 99%

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Sprague

Tio

Ahmed

et al. 2012

Circ: Cardiovascular Interventions

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D rug-eluting stents (DES) have dramatically reduced the long-term rate of reintervention and improved clinical outcomes among patients undergoing percutaneous coronary interventions.1 However, DES use still carries a small but critically important cumulative risk of late stent thrombosis. Human pathology studies suggest that delayed healing leads to incomplete strut coverage, which has been associated with late thrombotic events.2 Moreover, early DES platforms elicited enhanced platelet adhesion 3 and endothelial dysfunction. 4 Most DES technologies now embody thinner metallic platforms containing minimal amounts of polymeric drug formulations while maintaining drug concentrations and release profiles. 5,6 Although a slight decline in the overall stent thrombosis rate has been observed with the use of latest generation of DES platforms, these potentially lethal events still occur. Despite their efficacy in preventing restenosis, the antiproliferative effect of drugs used in commercially available DES appear to delay stent endothelialization. Technological approaches have been used to enhance stent endothelialization by modifying the stent surface with antibodies to selectively bind circulating endothelial progenitor cells. 7 An alternate strategy to encourage reendothelialization is to modify the stent surface to increase the natural rate of endothelial cell migration from adjacent arterial areas of intact healthy endothelium. Previous studies in our laboratory have shown that parallel microgrooves applied to the surface of different metals 8,9 increase the rate of human aortic endothelial cell migration by >2-fold compared with smooth coupons. More importantly, when this pattern was applied to the luminal surface of stents in an early pilot study, the endothelialization rate on these grooved stents was double compared with Background-Stent luminal surface characteristics influence surface endothelialization. We hypothesize that luminal stent microgrooves created in the direction of coronary flow accelerate endothelial cell migration, resulting in lower levels of neointimal formation. Methods and Results-Surface coverage efficiency was evaluated in vitro by allowing human aortic endothelial cells (HAEC) to migrate onto microgrooved (G) or smooth (NG) surfaces. HAEC functionality was assessed by proliferation rate, apoptosis rate, nitric oxide production, and inflammatory markers TNF-α and VCAM-1 expression. Early endothelialization and restenosis studies were performed using the porcine coronary injury model. Stainless steel stents of identical design with (GS) and without (NGS) luminal microgrooves were used. The commercially available Multi-Link Vision (MLVS) stent of identical design was used as a control. The degree of GS and NGS surface endothelialization was compared at 3 days. Biocompatibility and tissue response outcomes were evaluated at 28 days. The in vitro study demonstrated that at 7 days the presence of surface microgrooves increased HAEC migration distance >2-fold. Cell proliferation rate and nit...

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“…In some studies of human aortic endothelial cells, long-term exposure to high glucose (22-30 mmol/l) increased eNOS mRNA transcription (23) and basal NO production (24). In another study, the basal level of NO production and Ca 2ϩ -stimulated NO production were found unchanged after similar high-glucose exposure in the same model, but insulin-stimulated NO synthesis decreased (25).…”

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confidence: 94%

Compromised Arterial Function in Human Type 2 Diabetic Patients

et al. 2005

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Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr 308 and Ser 473 ) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr 308 ) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of N-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms. Diabetes 54:2415-2423, 2005

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High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration

Cited by 97 publications

References 26 publications

High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction

High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Compromised Arterial Function in Human Type 2 Diabetic Patients

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