The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S]
Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2009-04-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520308592 |
| _version_ | 1819077248978780160 |
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| author | Zory Shaposhnik Xuping Wang Joaquim Trias Heather Fraser Aldons J. Lusis |
| author_facet | Zory Shaposhnik Xuping Wang Joaquim Trias Heather Fraser Aldons J. Lusis |
| author_sort | Zory Shaposhnik |
| collection | DOAJ |
| description | Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE−/− mice were investigated. Male apoE−/− mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-α actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by ∼75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture. |
| first_indexed | 2024-12-21T18:54:11Z |
| format | Article |
| id | doaj.art-b7fc3c1c699a470fac6934cf3c9f7f67 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-21T18:54:11Z |
| publishDate | 2009-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-b7fc3c1c699a470fac6934cf3c9f7f672022-12-21T18:53:40ZengElsevierJournal of Lipid Research0022-22752009-04-01504623629The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S]Zory Shaposhnik0Xuping Wang1Joaquim Trias2Heather Fraser3Aldons J. Lusis4Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095; Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679; Anthera Pharmaceuticals, Inc., Hayward, CA 94545Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095; Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679; Anthera Pharmaceuticals, Inc., Hayward, CA 94545Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095; Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679; Anthera Pharmaceuticals, Inc., Hayward, CA 94545Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095; Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679; Anthera Pharmaceuticals, Inc., Hayward, CA 94545Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA 90095; Departments of Medicine, Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095-1679; Anthera Pharmaceuticals, Inc., Hayward, CA 94545Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE−/− mice were investigated. Male apoE−/− mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-α actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by ∼75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.http://www.sciencedirect.com/science/article/pii/S0022227520308592drugslipoproteinsvarespladibsecretory phospholipase A2 |
| spellingShingle | Zory Shaposhnik Xuping Wang Joaquim Trias Heather Fraser Aldons J. Lusis The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] Journal of Lipid Research drugs lipoproteins varespladib secretory phospholipase A2 |
| title | The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] |
| title_full | The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] |
| title_fullStr | The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] |
| title_full_unstemmed | The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] |
| title_short | The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)[S] |
| title_sort | synergistic inhibition of atherogenesis in apoe mice between pravastatin and the spla2 inhibitor varespladib a 002 s |
| topic | drugs lipoproteins varespladib secretory phospholipase A2 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520308592 |
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