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Circulation Research
Year: 2010  |  Volume: 106  |  Issue: 5  |  Page No.: 902 - 910

Lack of Mitogen-Activated Protein Kinase Phosphatase-1 Protects ApoE-Null Mice Against Atherosclerosis

J Shen, U. M Chandrasekharan, M. Z Ashraf, E Long, R. E Morton, Y Liu, J. D Smith and P. E. DiCorleto    


Rationale: Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.

Objective: To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.

Methods and Results: Mice with homozygous deficiency in MKP-1 (MKP-1–/–) were bred with apolipoprotein (Apo)E-deficient mice (ApoE–/–) and the 3 MKP-1 genotypes (MKP-1+/+/ApoE–/– ; MKP-1+/–/ApoE–/– and MKP-1–/–/ApoE–/–) were maintained on a normal chow diet for 16 weeks. The 3 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. Less en face lesion was observed in 8-month-old MKP-1–/– mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1 and tumor necrosis factor , and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1–null mice had higher levels of plasma stromal cell–derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immuno-histochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1–null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1–null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1–intact bone marrow into MKP-1–null mice fully rescued the wild-type atherosclerotic phenotype.

Conclusion: These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.

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