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Masanori aikawa powerpoint

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Masanori aikawa powerpoint

  1. 1. Masanori Aikawa, MD, PhD Peter Libby, MD Cardiovascular Medicine Brigham and Women’s Hospital Harvard Medical School Boston, MA The balance of power in “vulnerable” plaques: collagenases vs. collagen
  2. 2. Abstract Rupture of the “vulnerable” plaque often triggers acute coronary syndromes. Interstitial collagen determines plaque stability. We have demonstrated macrophage expression of collagenases (MMP-1, MMP-8 and MMP-13) in human and experimental atherosclerosis. Collagen degradation by collagenases may contribute to the vulnerability of atheroma. Lipid lowering in hypercholesterolemic rabbits reduces collagenase expression and ,in parallel, increases collagen in atheroma, suggesting a critical role of collagenase in collagen balance. We have recently found that collagenase-resistance alters collagen content in mouse atheroma. These results suggest that collagenase action regulates the collagen metabolism crucial to the clinical complications of atheroma.
  3. 3. M.L. Higuchi ThrombusThrombus ThinThin FibrousFibrous CapCap Lipid CoreLipid Core Rupture of the “vulnerable” atheroscleroticRupture of the “vulnerable” atherosclerotic plaque triggers acute coronary syndromesplaque triggers acute coronary syndromes
  4. 4. Atheromatous core Lipid, Macrophage-rich Proteolytic activity (MMPs) Prothrombotic activity (TF) Characterization of the “vulnerable” atherosclerotic plaque Lumen More stable plaque Adopted from Masanori Aikawa and Peter Libby, European Heart Journal 2001 Lumen Thin fibrous cap Collagen-poor
  5. 5. Degradadation fragments (3/4 & 1/4) Small peptides / Amino Acids Fibrillar collagen MMP-13 / collagenase-3 MMP-8 / collagenase-2 MMP-1 / collagenase-1 MMP-13 / collagenase-3 MMP-2 / gelatinase-A MMP-9 / gelatinase-B Collagen breakdown by collagenases may contribute to the vulnerability of atheroma
  6. 6. Lipid lowering by HMG-CoA reductase inhibitors reduces the incidence of acute coronary events probably by stabilization of “vulnerable” atherosclerotic plaques Major statin trialsCholesterollevels AverageHigh Primary prevention Secondary prevention WOSCOPS 4S AFCAPS/TexCAPS CARE Pravastatin 24% risk reduction Simvastatin 34% risk reduction Lovastatin 40% risk reduction Pravastatin 31% risk reduction LIPID Pravastatin 24% risk reduction From Gotto and Farmer in Heart Disease (Braunwald, Zipes, Libby), 6th ed., 2001
  7. 7. Quantitative changes Lesion size Luminal area Inward remodeling? ?? Atheromatous core Macrophage-rich Proteolytic activity (MMP) Prothrombotic activity (TF) Thin fibrous cap Collagen-poor Activated SMC (MMP, TF) Stabilization of “vulnerable” plaques by lipid lowering Lumen “Regression” “Stabilization” Activated EC VCAM-1, MCP-1 Masanori Aikawa and Peter Libby, European Heart Journal 2001 Qualitative or functional changes Macrophages MMPs, TF Collagen
  8. 8. Hypothesis 1 Do human and experimental atherosclerotic plaques contain collagenases?
  9. 9. Hypothesis 2 Does lipid lowering improve features associated with plaque vulnerability: (i.e, macrophage accumulation, collagenase expression, collagen content)?
  10. 10. Hypothesis 3 Does collagenolysis regulate collagen accumulation of atheroma in genetically-altered mice?
  11. 11. Macrophage expression of collagenases in human atheroma Galis ZS, et al. JCI 1994 Sukhova GK, et al. Circulation 2000 MMP-1 / Collagenase-1 MMP-13 / Collagenase-3 Macrophages
  12. 12. Cell-typeMMP-8 EC SMC MØ MMP-8/collagenase-2 expression by all cell types in human atheroma Herman et al. Circulation 2001
  13. 13. MMP-1/collagenase-1 expression in atheroma of cholesterol-fed rabbits Smooth muscle cells Macrophages MMP-1/collagenase-1 Masanori Aikawa, Elena Rabkin, Yoshikatsu Okada, Sami Voglic, Steven Clinton, Constance Brinckerhoff, Galina Sukhova, Peter Libby Circulation 1998;97:2433-2444
  14. 14. MMP-13/collagenase-3 expression by macrophages in atheroma of apoE-deficient mice MacrophagesMacrophages MMP-13 / collagenase-3MMP-13 / collagenase-3 Fukumoto, Libby, Rabkin, Deguchi, Varo, Harada, Hill, Lawler, Schoen, Krane, Aikawa. Unpublished data.
  15. 15. MMP-3/stromelysin-1 MMP-9/gelatinase-B MMP-3 and MMP-9 expression in atheroma of Watanabe heritable hyperlipidemic (WHHL) rabbits Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, Masanori Aikawa Circulation 2001;103:993-999
  16. 16. Dietary lipid lowering reduces macrophages, MMP expression, and increases collagen content (a key determinant of plaque stability) in atheroma of cholesterol-fed rabbits Masanori Aikawa, Elena Rabkin, Yoshikatsu Okada, Sami J. Voglic, Steven K. Clinton, Constance E. Brinckerhoff, Galina K. Sukhova, Peter Libby Circulation 1998;97:2433-2444 Decreased collagenase and increased collagen
  17. 17. Dietary lipid lowering reduces macrophages in atheroma of cholesterol-fed rabbits Baseline lesion After lipid lowering Masanori Aikawa, Elena Rabkin, Yoshikatsu Okada, Sami Voglic, Steven Clinton, Constance Brinckerhoff, Galina Sukhova, Peter Libby Circulation 1998;97:2433-2444
  18. 18. Collagen (Sirius red) Masanori Aikawa, Elena Rabkin, Yoshikatsu Okada, Sami J. Voglic, Steven K. Clinton, Constance E. Brinckerhoff, Galina K. Sukhova, Peter Libby Circulation 1998;97:2433-2444 Dietary lipid lowering reduces collagenase expression and increases collagen accumulation in atheroma of cholesterol-fed rabbits Baseline lesion Collagenase-1/MMP-1 Collagen After Lipid Lowering
  19. 19. Diet lipid lowering promotes accumulation of mature SMCs expressing less MMPs in atheroma of cholesterol-fed rabbits Masanori Aikawa, Elena Rabkin, Sami J. Voglic, Helen Shing, Ryozo Nagai, Frederick J. Schoen, Peter Libby Circulation Research 1998;83:1015-1026
  20. 20. Control GroupControl Group MMφφ MMP-1MMP-1 MMφφ MMP-1MMP-1 Cerivastatin GroupCerivastatin Group Cerivastatin reduces macrophage accumulation and MMP expression in atheroma of WHHL rabbits Masanori Aikawa, Elena Rabkin, Seigo Sugiyama, Sami J. Voglic, Yoshihiro Fukumoto, Yutaka Furukawa, Masashi Shiomi, Frederick J. Schoen, Peter Libby Circulation 2001;103:276-283 Plaque Stabilization by Statins 1 Effects on Evolution of Atheroma
  21. 21. Cerivastatin treatment reduces MMP expression by macrophages in atheroma of WHHL rabbits MMP-1/collagenase-1 MMP-9/gelatinase-BMMP-3/stromelysin-1 Masanori Aikawa, Elena Rabkin, Seigo Sugiyama, Sami Voglic, Yoshihiro Fukumoto, Yutaka Furukawa, Masashi Shiomi, Frederick J. Schoen, Peter Libby Circulation 2001;103:276-283 CerivastatinControl 0 10 20 30 40 50 p<0.01 0 20 40 60 80 CerivastatinControl 0 10 20 30 40 p<0.01 CerivastatinControl p<0.01 MMP-positivemacrophages(%) n=9 n=10 n=9 n=10n=9 n=10 Plaque Stabilization by Statins 1 Effects on Evolution of Atheroma
  22. 22. CerivastatinCerivastatin ControlControlCerivastatin increases interstitial collagen accumulation in atheroma of WHHL rabbits Picrosirius red polarizationPicrosirius red polarization Masanori Aikawa, Elena Rabkin, Seigo Sugiyama, Sami J. Voglic, Yoshihiro Fukumoto, Yutaka Furukawa, Masashi Shiomi, Frederick J. Schoen, Peter Libby Circulation 2001;103:276-283 Plaque Stabilization by Statins 1 Effects on Evolution of Atheroma
  23. 23. Pravastatin (hydrophilic) and fluvastatin (lipophilic) reduce MMP in macrophages in atheroma of WHHL rabbits to a similar extent MMP-1 (+) Mφ 100 Cont n=10 Prava n=9 Fluva n=10 0 50 % p<0.01 MMP-3 (+) Mφ Cont n=10 Prava n=9 Fluva n=10 0 50 100 % p<0.05 p<0.05 100 MMP-9 (+) Mφ Cont n=10 Prava n=9 Fluva n=10 0 50 % p<0.01 p<0.01 Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, Masanori Aikawa Circulation 2001;103:993-999 Plaque Stabilization by Statins 2 Differential Effects of Statins
  24. 24. Picrosirius Red Polarization Atheroma of pravastatin -treated WHHL rabbits contain more interstitial collagen than those treated with fluvastatin Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, Masanori Aikawa Circulation 2001;103:993-999 Control Pravastatin Fluvastatin Cont n=10 Prava n=9 Fluva n=10 0 5 10 15 p<0.01 p<0.01 %-positivearea Plaque Stabilization by Statins 2 Differential Effects of Statins
  25. 25. Pravastatin Fluvastatin Procollagen-I mRNA SMα-actin Pravastatin-treated WHHL rabbits contain more procollagen-I mRNA expression than those with fluvastatin treatment Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, Masanori Aikawa Circulation 2001;103:993-999
  26. 26. Diet Statins Lesion size………………………………...Decreased No change Macrophage accumulation……………..Decreased Decreased Macrophage proliferation………………. Decreased Macrophage apoptosis…………………. No change MMP expression/activity………………..Decreased Decreased Collagen accumulation………………….Increased Increased Tissue factor expression/activity……...Decreased Decreased PAI-1 expression…………………………. Decreased CD154 (CD40L) expression……………..Decreased Decreased PDGF-B expression………………………Decreased SMC differentiation……………………….Increased Lipid lowering in rabbit atheroma
  27. 27. Lipid lowering in rabbit atheroma Diet Statins apoB-100 accumulation…………………Decreased MDA accumulation……………………….Decreased Decreased ROS production…………………………..Decreased VCAM-1 expression……………………...Decreased MCP-1 expression………………………..Decreased eNOS expression………………………...Increased Microvessels.……………………………..Decreased Aikawa M, et al. Circulation 1998;97:2433-2444, Circ Res 1998;83:1015-1026, Circulation 1999;100:1215-1222, Circulation 2001;103:276-283, Circulation in revision Fukumoto Y, et al. Circulation 2001;103:993-999, Circulation in revision McConnell M, et al. Arterioscler Thromb Vasc Biol 1999;19:1956-1959
  28. 28. Collagen accumulation MMP-collagenases (MMP-1, MMP-13) Inverse relationship between collagenase expression and collagen content in atheroma during lipid lowering suggests the crucial role of collagenase in collagen balance. However, no direct evidence links collagenases with regulation of the collagen content of atheroma. ??
  29. 29. “Genetically-determined resistance to collagenase action alters content of collagen and smooth muscle cells in atheroma” Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Jun-o Deguchi, Nerea Varo, Koichiro Harada, Christopher C. Hill, Patrick R. Lawler, Frederick J. Schoen, Stephen M. Krane, Masanori Aikawa ACC2002 Young Investigator Awards Molecular and Cellular Cardiology Monday, March 18, 2 PMMonday, March 18, 2 PM Georgia World Congress Center, Room 257W In vivo direct evidence of the role of collagenase
  30. 30. Fibrillar collagen MMP-13 / collagenase-3 MMP-8 / collagenase-2 MMP-1 / collagenase-1 MMP-13 / collagenase-3 MMP-2 / gelatinase-A MMP-9 / gelatinase-B Collagenase-resistant mutant “knock-in” mouse Mutation at specific cleavage Site of type-I collagen for MMP-collagenases
  31. 31. Does collagenase-resistance preserve more collagen in mouse atheroma ? Col+/+ / apoE-/- ColR/R / apoE-/- ??
  32. 32. Conclusion Collagenases play a critical role in collagen metabolism in atheroma.
  33. 33. Acknowledgment Brigham and Women’s Hospital, Boston Yoshihiro Fukumoto Elena Rabkin Christopher C. Hill Sami J. Voglic Seigo Sugiyama Jun-o Deguchi Koichiro Harada Nerea Varo Patrick Lawler MGH, Boston Steve M, Krane Univ. of Tokyo Ryozo Nagai Kobe Univ. Masashi Shiomi USC, LA Alex Sevanian Yoshikatsu Okada Yutaka Furukawa Eugenia Shvartz Helen Shing Galina K. Sukhova Michael Herman Uwe Schoenbeck Frederick J. Schoen

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