Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide.
Due to their localization at the interface between blood and tissue, endothelial cells are the first target of any change occurring within the blood, and alterations of their functions can seriously impair organs. During hypoxia, which mimics in vivo ischemia, a cascade of events occurs in the endothelial cells, starting with a decrease in ATP content and leading to their activation and release of inflammatory mediators. EGb 761 and one of its constituents, bilobalide, were shown to inhibit the hypoxia-induced decrease in ATP content in endothelial cells in vitro. Under these conditions, glycolysis was activated, as evidenced by increased glucose transport, as well as increased lactate production. Bilobalide was found to increase glucose transport under normoxic but not hypoxic conditions. In addition, EGb and bilobalide prevented the increase in total lactate production observed after 60 min of hypoxia. However, after 120 min of hypoxia, the total lactate production was similar under normoxic and hypoxic conditions, and both compounds increased this production. These results indicate that glycolysis slowed down between the 60th and 120th minute of hypoxia, while EGb and bilobalide delayed the onset of glycolysis activation. In another experimental model, both compounds were shown to increase the respiratory control ratio of mitochondria isolated from liver of rats treated orally. Since ischemia is known to uncouple mitochondria, the protection of ATP content and the delay in glycolysis activation observed during hypoxia in the presence of EGb 761 or bilobalide is best explained by a protection of mitochondrial respiratory activity, at least during the first 60 min of hypoxia incubation. Both products retain the ability to form ATP, thereby reducing the cell's need to induce glycolysis, probably by preserving ATP regeneration by mitochondria as long as oxygen is available.
Janssens
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D
Laboratoire de Biochimie Cellulaire, Facultés Universitaires Notre Dame de la Paix, Namur, Belgium.
Michiels
C
C
Delaive
E
E
Eliaers
F
F
Drieu
K
K
Remacle
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D020441:Ginkgo biloba; D046934:Ginkgolides; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D000096983:Ginkgo Extract
D000255:Adenosine Triphosphate; D003517:Cyclopentanes; D004224:Diterpenes; D005663:Furans; D046934:Ginkgolides; D005947:Glucose; D007773:Lactates; D010936:Plant Extracts; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C073710:bilobalide