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(American Journal of Pathology. 2001;158:879-891.)
© 2001 American Society for Investigative Pathology

Regular Articles

Macrophage Myeloperoxidase Regulation by Granulocyte Macrophage Colony-Stimulating Factor in Human Atherosclerosis and Implications in Acute Coronary Syndromes

Seigo Sugiyama*, Yoshikatsu Okada*, Galina K. Sukhova*, Renu Virmani{dagger}, Jay W. Heinecke{ddagger} and Peter Libby*

From the Department of Medicine,*
Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; the Department of Cardiovascular Pathology,{dagger}
Armed Forces Institute of Pathology, Washington, District of Columbia; and the Department of Medicine,{ddagger}
Washington University School of Medicine, St. Louis, Missouri

Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased numbers of myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express myeloperoxidase and produce HOCl in vitro. Moreover, myeloperoxidase-positive macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl production by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage myeloperoxidase expression in human atherosclerosis and support a particular role for the myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes.




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Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes
Circulation, December 3, 2002; 106(23): 2894 - 2900.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
B. J. Van Lenten, A. C. Wagner, G.M. Anantharamaiah, D. W. Garber, M. C. Fishbein, L. Adhikary, D. P. Nayak, S. Hama, M. Navab, and A. M. Fogelman
Influenza Infection Promotes Macrophage Traffic Into Arteries of Mice That Is Prevented by D-4F, an Apolipoprotein A-I Mimetic Peptide
Circulation, August 27, 2002; 106(9): 1127 - 1132.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan
Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis
Circ. Res., August 23, 2002; 91(4): 281 - 291.
[Abstract] [Full Text] [PDF]

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 GutHome page
M Carlson, Y Raab, L Seveus, S Xu, R Hallgren, and P Venge
Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis
Gut, April 1, 2002; 50(4): 501 - 506.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
P. Libby, P. M. Ridker, and A. Maseri
Inflammation and Atherosclerosis
Circulation, March 5, 2002; 105(9): 1135 - 1143.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Shihabi, W.-G. Li, F. J. Miller Jr., and N. L. Weintraub
Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls
Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H797 - H802.
[Full Text] [PDF]

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 Am. J. Pathol.Home page
J. M. Upston, X. Niu, A. J. Brown, R. Mashima, H. Wang, R. Senthilmohan, A. J. Kettle, R. T. Dean, and R. Stocker
Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis
Am. J. Pathol., February 1, 2002; 160(2): 701 - 710.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
M. O. Pentikainen, K. Oorni, and P. T. Kovanen
Myeloperoxidase and Hypochlorite, but Not Copper Ions, Oxidize Heparin-Bound LDL Particles and Release Them From Heparin
Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1902 - 1908.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
K. E. Brown, E. M. Brunt, and J. W. Heinecke
Immunohistochemical Detection of Myeloperoxidase and Its Oxidation Products in Kupffer Cells of Human Liver
Am. J. Pathol., December 1, 2001; 159(6): 2081 - 2088.
[Abstract] [Full Text] [PDF]

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 JAMAHome page
R. Zhang, M.-L. Brennan, X. Fu, R. J. Aviles, G. L. Pearce, M. S. Penn, E. J. Topol, D. L. Sprecher, and S. L. Hazen
Association Between Myeloperoxidase Levels and Risk of Coronary Artery Disease
JAMA, November 7, 2001; 286(17): 2136 - 2142.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
S. PFEIFFER, A. LASS, K. SCHMIDT, and B. MAYER
Protein tyrosine nitration in mouse peritoneal macrophages activated in vitro and in vivo: evidence against an essential role of peroxynitrite
FASEB J, November 1, 2001; 15(13): 2355 - 2364.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
M. P. Herman, G. K. Sukhova, P. Libby, N. Gerdes, N. Tang, D. B. Horton, M. Kilbride, R. E. Breitbart, M. Chun, and U. Schonbeck
Expression of Neutrophil Collagenase (Matrix Metalloproteinase-8) in Human Atheroma: A Novel Collagenolytic Pathway Suggested by Transcriptional Profiling
Circulation, October 16, 2001; 104(16): 1899 - 1904.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
A. MERTENS and P. HOLVOET
Oxidized LDL and HDL: antagonists in atherothrombosis
FASEB J, October 1, 2001; 15(12): 2073 - 2084.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
E. Hurt-Camejo, G. Camejo, H. Peilot, K. Oorni, and P. Kovanen
Phospholipase A2 in Vascular Disease
Circ. Res., August 17, 2001; 89(4): 298 - 304.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Pfeiffer, A. Lass, K. Schmidt, and B. Mayer
Protein Tyrosine Nitration in Cytokine-activated Murine Macrophages. INVOLVEMENT OF A PEROXIDASE/NITRITE PATHWAY RATHER THAN PEROXYNITRITE
J. Biol. Chem., August 31, 2001; 276(36): 34051 - 34058.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
X. Fu, S. Y. Kassim, W. C. Parks, and J. W. Heinecke
Hypochlorous Acid Oxygenates the Cysteine Switch Domain of Pro-matrilysin (MMP-7). A MECHANISM FOR MATRIX METALLOPROTEINASE ACTIVATION AND ATHEROSCLEROTIC PLAQUE RUPTURE BY MYELOPEROXIDASE
J. Biol. Chem., October 26, 2001; 276(44): 41279 - 41287.
[Abstract] [Full Text] [PDF]


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