| First Author | Imaizumi S | Year | 2010 |
| Journal | Mol Genet Metab | Volume | 101 |
| Issue | 1 | Pages | 66-75 |
| PubMed ID | 20619710 | Mgi Jnum | J:164607 |
| Mgi Id | MGI:4834721 | Doi | 10.1016/j.ymgme.2010.05.009 |
| Citation | Imaizumi S, et al. (2010) Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels. Mol Genet Metab 101(1):66-75 |
| abstractText | RATIONALE: We previously reported that mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is necessary for oxidized phospholipids to induce monocyte chemoattractant protein-1 (MCP-1) secretion by human aortic endothelial cells. We also reported that inhibition of tyrosine phosphatases including MKP-1 ameliorated atherosclerotic lesions in mouse models of atherosclerosis. OBJECTIVE: This study was conducted to further investigate the specific role of MKP-1 in atherogenesis. METHODS AND RESULTS: We generated MKP-1(-/-)/apoE(-/-) double-knockout mice. At 24weeks of age, the size, macrophage and dendritic cell content of atherosclerotic lesions of the aortic root were significantly lower ( approximately -41% for lesions and macrophages, and approximately -78% for dendritic cells) in MKP-1(-/-)/apoE(-/-) mice when compared with apoE(-/-) mice. Total cholesterol (-18.4%, p=0.045) and very low-density lipoprotein (VLDL)/low-density lipoprotein (LDL) cholesterol (-20.0%, p=0.052) levels were decreased in MKP-1(-/-)/apoE(-/-) mice. Serum from MKP-1(-/-)/apoE(-/-) mice contained significantly lower levels of MCP-1 and possessed significantly reduced capability to induce monocyte migration in vitro. Moreover, peritoneal macrophages isolated from MKP-1(-/-)/apoE(-/-) mice produced significantly lower levels of MCP-1 when compared to peritoneal macrophages from apoE(-/-) mice. Furthermore, MKP-1(-/-)/apoE(-/-) mice had significantly reduced serum hydroxyeicosatetraenoic acids (HETEs) levels, which have been reported to induce MCP-1 levels. CONCLUSIONS: Our results demonstrate that MKP-1 deficiency significantly decreases atherosclerotic lesion development in mice, in part, by affecting MCP-1 levels in the circulation and MCP-1 production by macrophages. MKP-1 may serve as a potential therapeutic target for the treatment of atherosclerotic disease. |
