Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels

作者：Imaizumi Satoshi; Grijalva Victor; Priceman Saul; Wu Lily; Su Feng; Farias Eisner Robin; Hama Susan; Navab Mohamad; Fogelman Alan M; Reddy Srinivasa T^*

来源：Molecular Genetics and Metabolism, 2010, 101(1): 66-75.

DOI：10.1016/j.ymgme.2010.05.009

• Mitogen-activated protein kinase phosphatase-1
• Atherosclerosis
• Monocyte chemoattractant protein-1
• Monocytes

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 24 weeks of age, the size, macrophage and dendritic cell content of atherosclerotic lesions of the aortic root were significantly lower (similar to-41% for lesions and macrophages, and similar to-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 (DL) 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.

• 出版日期2010-9