SHAPE Society

1. Editorial Slides
VP Watch –June 19, 2002 - Volume 2, Issue 24
Propagermanium; A Potential Drug For Vulnerable
Plaque?

2.  Atherosclerosis is an inflammatory disease. 1
 Macrophage infiltration is essential in both
formation of atherosclerotic plaque as well as
their thrombotic complications.
 Monocyte chemoattractant protein-1 (MCP-1)
plays an important role in plaque inflammation. 2

3.  MCP-1 is the prototype of the C-C chemokine
ß subfamily and exhibits its most potent
chemotactic activity toward monocytes and T
lymphocytes. 4
 MCP-1 expression is induced by cytokines,
growth factors, or complement factors in
monocytes, endothelial cells, and vascular
SMCs. 4,5

4.  Increased MCP-1 expression has been
detected in atherosclerotic lesions but not in
normal arteries. 2,3
 Boring and coworkers showed that selective
absence of CCR2 (MCP-1 receptor) decreased
plaque formation markedly in apoE-/- mice but
has no effect on plasma lipid or lipoprotein
concentrations. 6

5.  This group also showed that activation of CCR2
was important in recruitment of monocytes
/macrophages into the vessel wall, the earliest
recognizable sign of atherosclerosis. 6
 Anti–MCP-1 gene therapy using a deletion
mutant of human MCP-1 gene inhibits the
formation of atherosclerosis in apoE-KO mice.

6.  As reported in VP Watch of this week,
Yamashita, Yokoyama, and colleagues
showed the effect of propagermanium (an
organic germanium compound previously used
for the treatment of chronic hepatitis), on
atherosclerosis. 7
 They found that propagermanium, which
inhibits macrophage infiltration through the
suppression of CCR2 (MCP-1 receptor)
function, significantly reduces atherosclerosis
in apoE deficient mice. 7

7.  They also found fewer macrophages in
atherosclerotic plaques of propagermanium
-treated apoE deficient mice compared to
plentiful macrophages in subendothelial area
of plaques in control groups. 7
 Propagermanium does not affect the plasma
MCP-1 levels in cholesterol-fed apoE-KO
mice. 7

8. Reduced Atherosclerotic Lesions of ApoE-
KO Mice Treated With Propagermanium
0.00
0.50
1.00
1.50
2.00
2.50
Control Group (8w) Drug Group (8w)
0.00
0.50
1.00
1.50
2.00
2.50
Control Group (12w) Drug Group (12w)
Quantitative analysis of atherosclerotic lesion in the control group and
drug group (open bar). Total lesion area of 5 sections in the aortic root
from each mouse was calculated. Values are mean±SEM of at least 8
mice in each group. *P<0.05 and **P<0.01 vs control group.
TotalLesionAreamm2
Tomoya Yamashita, Seinosuke Kawashima, Masanori Ozaki, Masayuki Namiki, Nobutaka Inoue, Ken-ichi Hirata, and Mitsuhiro Yokoyama;
Propagermanium Reduces Atherosclerosis in Apolipoprotein E Knockout Mice via Inhibition of Macrophage Infiltration. Arterioscler Thromb Vasc Biol
2002 22: 969 - 974
TotalLesionAreamm2
8 Weeks 12 Weeks

9.  The present study exhibited that
propagermanium markedly attenuates
the MCP-1–induced adhesion of J774.1
cells to the endothelium in vitro and also
reduces the thioglycollate-induced
macrophage infiltration to the abdominal
cavity in vivo. 7

10. Conclusion
• Propagermanium attenuates
atherogenesis via the inhibition of
macrophage infiltration in apoE-KO mice.
• The MCP-1/CCR2 pathway would be a
promising therapeutic target in the
prevention of atherosclerosis.

11. Questions:
• Does propagermanium similarly affect
macrophage infiltration in old apoE
deficient mice?
• Is it effective in early stage plaque
formation as well as late stage plaque
complication (rupture and
thrombosis)?

12. Questions:
• Since propagermanium is a competitive
inhibitor of MCP-1 receptor and does not
affect serum MCP-1, would local drug
delivery of propagermanium
(propagermanium-coated stent) provide
additional benefit for treatment of
vulnerable plaques?

13. 1) Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340:115–126.
2) Terkeltaub R, Boisvert WA, Curtiss LK. Chemokines and atherosclerosis. Curr Opin Lipidol. 1998; 9: 397–405
3) Ylä-Herttuala S, Lipton BA, Rosenfeld ME, Sarkioja T, Yoshimura T, Leonard EJ, Witztum JL, Steinberg D. Expression of monocyte
chemoattractant protein-1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991; 88:
5252–5256.
4) Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today.
1996; 2: 198–204
5) Torzewski J, Oldroyd R, Lachmann PJ, Fitzsimmons CJ, Proudfoot D, Bowyer DE. Complement-induced release of monocyte
chemotactic protein 1 from human SMC: a possible initiating event in atherosclerotic lesion formation. Arterioscler Thromb Vasc Biol.
1996; 16: 673–677
6) Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of
atherosclerosis. Nature. 1998; 394: 984–897.
7) Tomoya Yamashita, Seinosuke Kawashima, Masanori Ozaki, Masayuki Namiki, Nobutaka Inoue, Ken-ichi Hirata, and Mitsuhiro
Yokoyama; Propagermanium Reduces Atherosclerosis in Apolipoprotein E Knockout Mice via Inhibition of Macrophage Infiltration.
Arterioscler Thromb Vasc Biol 2002 22: 969 - 974
References