|Title:||Electronegative LDL impairs vascular endothelial cell integrity in diabetes by disrupting fibroblast growth factor 2 (FGF2) autoregulation||Authors:||Lu J.
|Issue Date:||2008||Journal Volume:||57||Journal Issue:||1||Start page/Pages:||158-166||Source:||Diabetes||Abstract:||
OBJECTIVE - L5, a circulating electronegative LDL identified in patients with hypercholesterolemia or type 2 diabetes, induces endothelial cell (EC) apoptosis by suppressing fibroblast growth factor (FGF)2 expression. FGF2 plays a pivotal role in endothelial regeneration and compensatory arteriogenesis. It is likely that vasculopathy and poor collateralization in diabetes is a result of FGF2 dysregulation. RESEARCH DESIGN AND METHODS - To investigate this mechanism, we isolated L5 from type 2 diabetic patients. In cultured bovine aortic ECs (BAECs), L5 inhibited FGF2 transcription and induced apoptosis. Because FGF2 stimulates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, we examined whether FGF2 transcription is regulated by Akt through a feedback mechanism. RESULTS - Diabetic L5 reduced FGF2 release to the medium but enhanced caspase-3 activity, with resultant apoptosis. Inhibition of PI3K with wortmannin or suppression of Akt activation with dominant-negative Akt inhibited FGF2 expression. Transfection of BAECs with FGF2 antisense cDNA depleted endogenous FGF2 protein. In these cells, not only was Akt phosphorylation inhibited, but FGF2 transcription was also critically impaired. In contrast, transfecting BAECs with FGF2 sense cDNA augmented Akt phosphorylation. Treatment with constitutively active Akt enhanced FGF2 expression. Augmentation of either FGF2 transcription or Akt phosphorylation rendered BAECs resistant to L5. CONCLUSIONS - These findings suggest that FGF2 is the primary initiator of its own expression, which is autoregulated through a novel FGF2-PI3K-Akt loop. Thus, by disrupting FGF2 autoregulation in vascular ECs, L5 may impair reendothelialization and collateralization in diabetes. ? 2008 by the American Diabetes Association.
|ISSN:||0012-1797||DOI:||10.2337/db07-1287||SDG/Keyword:||caspase 3; complementary DNA; fibroblast growth factor 2; low density lipoprotein; phosphatidylinositol 3 kinase; protein kinase B; vasculotropin; wortmannin; fibroblast growth factor 2; low density lipoprotein; oxidized low density lipoprotein; vasculotropin A; animal cell; article; autoregulation; cell culture; cell isolation; cell survival; controlled study; drug inhibition; enzyme activity; enzyme linked immunosorbent assay; gene control; genetic transcription; genetic transfection; human; human cell; non insulin dependent diabetes mellitus; nonhuman; Northern blotting; priority journal; protein expression; protein phosphorylation; vascular endothelium; Western blotting; animal; aorta; apoptosis; blood; cattle; cytology; drug effect; gene expression; homeostasis; isolation and purification; pathology; pathophysiology; physiology; reference value; vascular endothelium; Animals; Aorta; Apoptosis; Cattle; Diabetes Mellitus, Type 2; Endothelium, Vascular; Fibroblast Growth Factor 2; Gene Expression; Homeostasis; Humans; Lipoproteins, LDL; Reference Values; Vascular Endothelial Growth Factor A
|Appears in Collections:||醫學系|
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