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.
Objective
This study was conducted to further investigate the specific role of MKP-1 in atherogenesis.
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.