Résumé
Objective— Mitogen-activated protein kinase phosphatase-1 (MKP-1) is one of several oxidized- l -α-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC)-induced genes identified in human aortic endothelial cells (HAEC). We previously reported that MKP-1 activity is required for Ox-PAPC–mediated endothelial/monocyte interactions; however, an in vivo role of MKP-1 in atherogenesis has not been investigated. Methods and Results— We now report that MKP-1 protein is expressed in the atherosclerotic lesions of mice. MKP-1 mRNA expression is highly induced in C57BL6/J mice on an atherogenic diet, low-density lipoprotein receptor (LDLR) (−/−) mice on a Western diet, and 10-week or older ApoE (−/−) mice on a chow diet. In ApoE (−/−) mice treated with 1 mg/mL of sodium orthovanadate (NaOV), a specific inhibitor of tyrosine phosphatases including MKP-1, total phosphatase activity and MKP-1 protein were decreased in both the aortic lesions and liver lysates. In 3 animal models of atherosclerosis [C57BL6/J mice on an atherogenic diet for 15 weeks, LDLR (−/−) mice on a Western diet for 10 weeks, and ApoE (−/−) mice on a chow diet for 8 weeks], mice treated with NaOV had significantly smaller atherosclerotic lesions when compared with the control group. Conclusion— MKP-1 expression is associated with hypercholesterolemia and atherosclerosis, and inhibition of MKP-1 activity may prevent atherosclerotic lesion development in mice. MKP-1 is required for Ox-PAPC–mediated endothelial/monocyte interactions; however, an in vivo role of MKP-1 in atherogenesis has not been investigated. We now report that MKP-1 protein is expressed in the atherosclerotic lesions of mice and inhibition of tyrosine phosphatase activity and MKP-1 protein reduce atherosclerotic lesions in mouse models.