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

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Editorial Slides VP Watch –June 19, 2002 - Volume 2, Issue 24

Propagermanium; A Potential Drug For Vulnerable Plaque?

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

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

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

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.

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

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

Reduced Atherosclerotic Lesions of ApoE-KO Mice Treated With Propagermanium

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Control Group (8w) Drug Group (8w)

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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.

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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

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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

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.

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)?

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?

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