MAP Kinase Phosphatase‐1 (MKP‐1) Deficiency Leads to Reduced Atherosclerotic Lesion Formation in ApoE‐null Mice

Abstract

Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts ‐ the protein phosphatases. We tested the hypothesis that Mitogen‐Activated Protein Kinase Phosphatase‐1 (MKP‐1), a negative regulator of MAPK signaling pathways, is actively involved in atherogenesis. Mice with homozygous deficiency in MKP‐1 (MKP‐1<−/−>) were bred with apoE‐deficient mice (apoE<−/−>) and the three MKP‐1 genotypes were maintained on a normal chow diet for 16 weeks. The three groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP‐1<+/−> and MKP‐1<−/−> mice had significantly less aortic root atherosclerotic lesion formation than MKP‐1<+/+> mice. Protein array analysis and Luminex bead‐based multiplexing assays showed that the reduction in atherosclerosis was accompanied by decreased serum levels of multiple pro‐inflammatory cytokines and chemokines, including IL‐1a and TNFa; whereas, the level of the anti‐inflammatory cytokine IL‐10 was not changed. Immuno‐histochemical analysis revealed that MKP‐1 protein expression was restricted to the macrophage‐rich, versus smooth muscle cell‐rich regions of the atheroma. Our results provide evidence for a pro‐atherosclerotic role of MKP‐1 via mechanisms independent of lipid metabolism and likely involving macrophage‐mediated inflammation. Support: NIH HL29582.