Abstract
BackgroundChronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation.Materials and methodsHuman aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated.ResultsEither high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes.ConclusionsLong-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.
Highlights
In the early stages of atherogenesis, the adhesiveness of vascular endothelium to monocytes is increased, which may be mediated by endothelial expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and others as a result of endothelial dysfunction [1]
Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia
High glucose time-dependently increases ICAM-1 and IL-6 expression in HEACs It has not been clarified which adhesion molecules such as ICAM-1, VCAM-1 or both and which cytokines might be involved in glucose-induced monocyte adhesion to endothelial cells [17]
Summary
In the early stages of atherogenesis, the adhesiveness of vascular endothelium to monocytes is increased, which may be mediated by endothelial expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and others as a result of endothelial dysfunction [1]. The detailed mechanisms by which high glucose could induce endothelial adhesiveness have not been fully clarified. VCAM-1 expression was shown to increase in endothelial cells by serum from type 1 diabetic patients but not by high-glucose stimulation [7]. Previous studies further indicated that the short-term presence of inflammatory cytokines rather than high glucose could induce endothelial expression of VCAM-1 and ICAM-1 [8]. The mechanisms of high-glucose-induced endothelial expression of adhesion molecules could be complex. Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation
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