title: High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration.
abstract: Delayed wound healing and accelerated atherosclerosis are common vascular complications of diabetes mellitus. Although elevated blood glucose level is the major contributing factor, mechanisms that mediate these complications are not clearly understood. In the present study, we have demonstrated that elevated glucose inhibits endothelial cell migration, thereby delaying wound healing. Our results clearly indicated that high glucose (10 or 30 mM) induced activation of nuclear factor kappa B (NF-kappaB) inhibited endothelial cell migration (P<0.05). High glucose induced NF-kappaB DNA binding activity may mediate this inhibition of migration by regulating intracellular nitric oxide. In vitro wound healing model in human aortic endothelial cells (HAEC) were used to evaluate cell migration under the influence of high glucose. The migration inhibited by high glucose was restored by NF-kappaB inhibitors (including E3-4-methylphenyl sulfonyl-2-propenenitrile, N-tosyl-Lys-chloromethylketone (TLCK), or over-expression of inhibitor subunit of kappaB) and endothelial nitric oxide synthase inhibitors (N-methyl-L-arginine (L-NMMA); and Nomega-nitro-L-arginine methyl ester (L-NAME)). Furthermore, NF-kappaB inhibitors attenuated high glucose induced eNOS expression and intracellular nitric oxide (NO) production. Cytoskeletal immunofluorescence staining confirmed differences in actin distribution in HAEC incubated in high glucose in the presence or absence of NF-kappaB and NO inhibitors, explaining the differences observed in migration. In summary, our results for the first time suggest therapeutic strategies involving inhibition of NF-kappaB activation induced by high glucose, which may improve wound healing and help avoid some of the vascular complications of diabetes.
authors: Department of Pathology, University of Texas Health Science Center at San Antonio, 78229, USA.
authors: Masao
authors: M
authors: Hamuro
authors: Jodie
authors: J
authors: Polan
authors: Mohan
authors: M
authors: Natarajan
authors: Sumathy
authors: S
authors: Mohan
mesh_terms: D000199:Actins / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009570:Nitriles; D009930:Organic Chemicals; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013450:Sulfones; D013997:Time Factors; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000199:Actins; D000970:Antineoplastic Agents; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D014107:Tosyllysine Chloromethyl Ketone; D009569:Nitric Oxide; D004247:DNA; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005947:Glucose