Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 48, Issue 4-5, Pages 803-811Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2013.01.002
Keywords
Adhesion molecule; Endothelial nitric oxide synthase; Ginkgo biloba extract; Heme oxygenase-1; High glucose; Reactive oxygen species
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Funding
- National Science Council [NSC 97-2314-B-075-039, NSC 98-2314-B-075-035, NSC 99-2314-B-182-042-MY3]
- UST-UCSD International Center of Excellence in Advanced Bio-engineering from the National Science Council [NSC-99-2911-1-009-101]
- Taipei Veterans General Hospital [VGH-V98B1-003, VGH-V100E2-002]
- Ministry of Education Aim for the Top University Plan
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Aim: Hyperglycemia is one of the major risk factors leading to vascular complications in clinical diabetes mellitus. Ginkgo biloba extract (GBE), an antioxidant herbal medicine, possesses anti-inflammatory effects. We examined whether GBE can reduce high glucose-induced endothelial adhesiveness to monocytes, an in vitro sign mimicking in vivo early atherogenesis, through selective regulation of heme oxygenase (HO)-1 expression. Methods: Human aortic endothelial cells (HAECs) were cultured with normal glucose or high glucose (25 mM) for 4 days and subsequently combined with GBE (EGb761, Dr. Willmar Schwabe, Karlsruhe, Germany) treatment in the last 18 h of the 4-day period. The endothelial reactive oxygen species (ROS) generation, adhesion molecule expression and the adhesiveness to monocytes were examined. The specific signal pathways such as HO-1 were also examined. Results: High glucose increased ROS generation, adhesion molecule expression and the adhesiveness to monocytes in HAECs. These high glucose-induced phenomena could be suppressed by GBE (100 mu g/ml)-induced HO-1 expression in a dose-dependent and time-dependent manner. In addition, jun N-terminal kinases inhibitor or phosphoinositide 3 kinase inhibitor could reduce GBE-induced HO-1 expression. Furthermore, HO-1 inhibitor, HO-1 siRNA, endothelial nitric oxide synthase (eNOS) siRNA, or nuclear factor erythroid 2-related factor (Nrf) 2 siRNA blocked the cytoprotective effects of GBE. Meanwhile, p38/mitogen-activated protein kinase (MAPK) inhibitor could also reduce the effects of GBE on HO-1 induction. Conclusion: GBE could reduce high glucose-induced endothelial adhesion via enhancing HO-1 expression through the Akt/eNOS and p38/MAPK pathways. Our findings suggest a potential strategy targeting on HO-1 induction by GBE for endothelial protection in the presence of high glucose such as that in diabetes mellitus. (C) 2013 Elsevier B.V. All rights reserved.
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