Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration.
Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62+/-0.12 versus 1.27+/-0.07 mm2, respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23+/-0.06 mm2 [drug-treated group] versus 0.67+/-0.07 mm2 [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.
Yamashita
Tomoya
T
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Kawashima
Seinosuke
S
Ozaki
Masanori
M
Namiki
Masayuki
M
Inoue
Nobutaka
N
Hirata
Ken-ichi
K
Yokoyama
Mitsuhiro
M
D000005:Abdomen; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000502:physiology; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D005857:Germanium / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009942:Organometallic Compounds / Q000627:therapeutic use*; D011422:Propionates; D013864:Thioglycolates / Q000494:pharmacology
D001057:Apolipoproteins E; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D008055:Lipids; D009942:Organometallic Compounds; D011422:Propionates; D013864:Thioglycolates; D005857:Germanium; C066750:propagermanium