Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody

E. Lutgens; B.C.G. Faber; K.B. Schapira; C.T. Evelo; R. van Haaften; S. Heeneman; K.B.J.M. Cleutjens; A.P.J.J. Bijnens; L. Beckers; J.G. Porter; C.R. Mackay; P. Rennert; V. Bailly; M. Jarpe; B. Dolinski; V. Koteliansky; T. de Fougerolles; M.J. Daemen

doi:10.1161/CIRCULATIONAHA.104.510073

Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody

E. Lutgens, B.C.G. Faber, K.B. Schapira, C.T. Evelo, R. van Haaften, S. Heeneman, K.B.J.M. Cleutjens, A.P.J.J. Bijnens, L. Beckers, J.G. Porter, C.R. Mackay, P. Rennert, V. Bailly, M. Jarpe, B. Dolinski, V. Koteliansky, T. de Fougerolles, M.J. Daemen

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. METHODS AND RESULTS: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2x) expressed in at least 1 group compared with a common reference (ApoE-/-, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression-dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1alpha, and MIP-1beta. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1alpha located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE-/- mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. CONCLUSIONS: Gene profiling of atherosclerotic plaque progression in ApoE-/- mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.

Original language	English
Pages (from-to)	3443-3452
Journal	Circulation
Volume	111
Issue number	25
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.104.510073
Publication status	Published - 1 Jan 2005

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10.1161/CIRCULATIONAHA.104.510073

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Lutgens, E., Faber, B. C. G., Schapira, K. B., Evelo, C. T., van Haaften, R., Heeneman, S., Cleutjens, K. B. J. M., Bijnens, A. P. J. J., Beckers, L., Porter, J. G., Mackay, C. R., Rennert, P., Bailly, V., Jarpe, M., Dolinski, B., Koteliansky, V., de Fougerolles, T., & Daemen, M. J. (2005). Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody. Circulation, 111(25), 3443-3452. https://doi.org/10.1161/CIRCULATIONAHA.104.510073

Lutgens, E. ; Faber, B.C.G. ; Schapira, K.B. ; Evelo, C.T. ; van Haaften, R. ; Heeneman, S. ; Cleutjens, K.B.J.M. ; Bijnens, A.P.J.J. ; Beckers, L. ; Porter, J.G. ; Mackay, C.R. ; Rennert, P. ; Bailly, V. ; Jarpe, M. ; Dolinski, B. ; Koteliansky, V. ; de Fougerolles, T. ; Daemen, M.J. / Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody. In: Circulation. 2005 ; Vol. 111, No. 25. pp. 3443-3452.

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title = "Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody",

abstract = "BACKGROUND: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. METHODS AND RESULTS: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2x) expressed in at least 1 group compared with a common reference (ApoE-/-, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression-dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1alpha, and MIP-1beta. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1alpha located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE-/- mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. CONCLUSIONS: Gene profiling of atherosclerotic plaque progression in ApoE-/- mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.",

author = "E. Lutgens and B.C.G. Faber and K.B. Schapira and C.T. Evelo and {van Haaften}, R. and S. Heeneman and K.B.J.M. Cleutjens and A.P.J.J. Bijnens and L. Beckers and J.G. Porter and C.R. Mackay and P. Rennert and V. Bailly and M. Jarpe and B. Dolinski and V. Koteliansky and {de Fougerolles}, T. and M.J. Daemen",

year = "2005",

month = jan,

day = "1",

doi = "10.1161/CIRCULATIONAHA.104.510073",

language = "English",

volume = "111",

pages = "3443--3452",

journal = "Circulation",

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Lutgens, E, Faber, BCG, Schapira, KB, Evelo, CT, van Haaften, R, Heeneman, S , Cleutjens, KBJM, Bijnens, APJJ, Beckers, L, Porter, JG, Mackay, CR, Rennert, P, Bailly, V, Jarpe, M, Dolinski, B, Koteliansky, V, de Fougerolles, T & Daemen, MJ 2005, 'Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody', Circulation, vol. 111, no. 25, pp. 3443-3452. https://doi.org/10.1161/CIRCULATIONAHA.104.510073

Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody. / Lutgens, E.; Faber, B.C.G.; Schapira, K.B.; Evelo, C.T.; van Haaften, R.; Heeneman, S.; Cleutjens, K.B.J.M.; Bijnens, A.P.J.J.; Beckers, L.; Porter, J.G.; Mackay, C.R.; Rennert, P.; Bailly, V.; Jarpe, M.; Dolinski, B.; Koteliansky, V.; de Fougerolles, T.; Daemen, M.J.

In: Circulation, Vol. 111, No. 25, 01.01.2005, p. 3443-3452.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody

AU - Lutgens, E.

AU - Faber, B.C.G.

AU - Schapira, K.B.

AU - Evelo, C.T.

AU - van Haaften, R.

AU - Heeneman, S.

AU - Cleutjens, K.B.J.M.

AU - Bijnens, A.P.J.J.

AU - Beckers, L.

AU - Porter, J.G.

AU - Mackay, C.R.

AU - Rennert, P.

AU - Bailly, V.

AU - Jarpe, M.

AU - Dolinski, B.

AU - Koteliansky, V.

AU - de Fougerolles, T.

AU - Daemen, M.J.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - BACKGROUND: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. METHODS AND RESULTS: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2x) expressed in at least 1 group compared with a common reference (ApoE-/-, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression-dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1alpha, and MIP-1beta. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1alpha located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE-/- mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. CONCLUSIONS: Gene profiling of atherosclerotic plaque progression in ApoE-/- mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.

AB - BACKGROUND: Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. METHODS AND RESULTS: Microarray analysis was performed on mRNA of aortic arches of ApoE-/- mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2x) expressed in at least 1 group compared with a common reference (ApoE-/-, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression-dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1alpha, and MIP-1beta. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1alpha located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE-/- mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. CONCLUSIONS: Gene profiling of atherosclerotic plaque progression in ApoE-/- mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.

U2 - 10.1161/CIRCULATIONAHA.104.510073

DO - 10.1161/CIRCULATIONAHA.104.510073

M3 - Article

VL - 111

SP - 3443

EP - 3452

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 25

ER -