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

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 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 (~-41% for lesions and macropahges, and ~-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) (-20.0%, p=0.052) cholesterol 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.

Molecular Biology of Atherosclerosis

“…The result seems paradoxical (1612). Confirmed by second study (820). Both groups concurred that the atherosclerosis protection was due to macrophage effects with less MCP-1 produced by MKP-1 Ϫ/Ϫ macrophages and less influx of inflammatory macrophages into lesions.…”

“…MKP-1 KO mice transplanted with wild-type bone marrow had slightly greater (though nonsignificant) atherosclerosis compared wild-type mice receiving wild-type bone marrow, suggesting only mild, if any, effects due to MKP-1 deficiency in the vessel wall (1612). However, macrophages from MKP-1-deficient mice were found to have impaired ERK1/2 expression and marked defects in their ability to spread and migrate, and reduced MCP-1 production, resulting in a reduction in lesion macrophage content (820,1612).…”

“…MKP-1 is a dualspecificity phosphatase that can deactivate all MAPK but preferentially p38 and JNK. While inhibition of these MAPK would seemingly be anti-inflammatory and therefore atheroprotective, MKP-1 deficiency was, in fact, found to decrease atherosclerosis (820,1612). MKP-1 KO mice transplanted with wild-type bone marrow had slightly greater (though nonsignificant) atherosclerosis compared wild-type mice receiving wild-type bone marrow, suggesting only mild, if any, effects due to MKP-1 deficiency in the vessel wall (1612).…”

“…In MKP-1 deficiency, an unknown mechanism led to impaired ERK1/2 expression which was linked to defective migration, an unexpected anti-inflammatory effect on macrophages (820,1612). In ASK1 KO, there was less early macrophage apoptosis and hence larger lesions (2005).…”

Mitogen-activated protein kinase phosphatase 1 (MKP-1) in macrophage biology and cardiovascular disease. A redox-regulated master controller of monocyte function and macrophage phenotype

“…As we have reviewed above, macrophage chemotaxis [110, 111], autophagy [129], apoptosis [127, 128] and activation [135–137] are mediated by mitogen-activated protein kinase (MAPK) pathways, which in turn are counter-regulated by MKP-1 [21, 22]. Two earlier reports had suggested that complete MKP-1 deficiency in apolipoprotein E-null (apoE −/− ) mice is atheroprotective [138, 139]. While it is possible that these partial atheroprotective properties of complete MKP-1 deficiency reported in apoE −/− mice are related specifically to apoE deficiency, a more likely explanation is that MKP-1 plays different roles in different cell types.…”