Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
| Autor: | Arianna Marino, Giuseppe Pugliese, Marta Letizia Hribal, Viviana Casagrande, Rossella Menghini, Paolo Gentileschi, Orazio Schillaci, Massimo Federici, Paolo Sbraccia, Valentina Marchetti, Michele Cavalera, Davide Lauro, Stefano Menini, Marta Fabrizi, Ottavia Porzio, Renato Lauro |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Pathology medicine.medical_specialty Settore MED/09 - Medicina Interna Stromal cell Mice Transgenic 030204 cardiovascular system & hematology Biology metalloproteinases Settore MED/13 - Endocrinologia Mice 03 medical and health sciences 0302 clinical medicine atherosclerosis inflammation lipotoxicity macrophages medicine Animals Macrophage Settore MED/49 - Scienze Tecniche Dietetiche Applicate Promoter Regions Genetic Receptor 030304 developmental biology Mice Knockout Tissue Inhibitor of Metalloproteinase-3 0303 health sciences Settore BIO/12 Macrophages Monocyte Tissue inhibitor of metalloproteinase Atherosclerosis Molecular biology Up-Regulation Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Receptors LDL Knockout mouse LDL receptor Diet Atherogenic Cardiology and Cardiovascular Medicine Lipoprotein |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology; Vol 32 Arteriosclerosis, Thrombosis, and Vascular Biology |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/macrophage cells. To investigate the role of TIMP3 in atherosclerosis, we generated a new mouse model in which Timp3 was overexpressed in the atherosclerotic plaque via a macrophage-specific promoter (MacT3). We elucidated any potential antiatherosclerotic effects of TIMP3, including regulation of monocyte/macrophage recruitment within atherosclerotic plaques, in MacT3 mice crossbred with low-density lipoprotein receptor knockout (LDLR −/− ) mice. Methods and Results— MacT3/LDLR −/− mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR −/− . En face aorta and aortic root examination of MacT3/LDLR −/− mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR −/− mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas. Conclusion— Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice. |
| Databáze: | OpenAIRE |
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