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229 propagermanium

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229 propagermanium

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

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