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, 2010 Sep.
Article
em En
| MEDLINE
| ID: mdl-20619710
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quimiocina CCL2
/
Aterosclerose
/
Fosfatase 1 de Especificidade Dupla
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article