EGb761 ameliorates the formation of foam cells by regulating the expression of SR-A and ABCA1: role of haem oxygenase-1.
OBJECTIVE
Accumulation of foam cells in the intima is a hallmark of early-stage atherosclerotic lesions. Ginkgo biloba extract (EGb761) has been reported to exert anti-oxidative and anti-inflammatory properties in atherosclerosis, yet the significance and the molecular mechanisms of action of EGb761 in the formation of macrophage foam cells are not fully understood.


RESULTS
Treatment with EGb761 resulted in a dose-dependent decrease in oxidized low-density lipoprotein (oxLDL)-mediated cholesterol accumulation in macrophages, a consequence that was due to a decrease in cholesterol uptake and an increase in cholesterol efflux. Additionally, EGb761 significantly down-regulated the mRNA and protein expression of class A scavenger receptor (SR-A) by decreasing expression of activator protein 1 (AP-1); however, EGb761 increased the protein stability of ATP-binding cassette transporter A1 (ABCA1) by reducing calpain activity without affecting ABCA1 mRNA expression. Small interfering RNA (siRNA) targeting haem oxygenase-1 (HO-1) abolished the EGb761-induced protective effects on the expression of AP-1, SR-A, ABCA1, and calpain activity. Accordingly, EGb761-mediated suppression of lipid accumulation in foam cells was also abrogated by HO-1 siRNA. Moreover, the lesion size of atherosclerosis was smaller in EGb761-treated, apolipoprotein E-deficient mice compared with the vehicle-treated mice, and the expression of HO-1, SR-A, and ABCA1 in aortas was modulated similar to that observed in macrophages.


CONCLUSIONS
These findings suggest that EGb761 confers a protection from the formation of foam cells by a novel HO-1-dependent regulation of cholesterol homeostasis in macrophages.
Tsai
Jin-Yi
JY
Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
Su
Kuo-Hui
KH
Shyue
Song-Kun
SK
Kou
Yu Ru
YR
Yu
Yuan-Bin
YB
Hsiao
Sheng-Huang
SH
Chiang
An-Na
AN
Wu
Yuh-Lin
YL
Ching
Li-Chieh
LC
Lee
Tzong-Shyuan
TS
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002154:Calpain / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D020441:Ginkgo biloba; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010936:Plant Extracts / Q000494:pharmacology*; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D000096983:Ginkgo Extract
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D002154:Calpain; D002784:Cholesterol; D051547:Heme Oxygenase-1; D010936:Plant Extracts; D051117:Scavenger Receptors, Class A; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract