Published online before print July 8, 2004, doi: 10.1161/01.ATV.0000138342.94314.64
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Potential Role for Mitogen-Activated Protein Kinase Phosphatase-1 in the Development of Atherosclerotic Lesions in Mouse Models
From the Atherosclerosis Research Unit (S.T.R., J.T.N., V.G., G.H., S.H., M.N., A.M.F.), Division of Cardiology, Department of Medicine, and the Department of Molecular and Medical Pharmacology (S.T.R.), University of California, Los Angeles, Calif.
Correspondence to Dr Srinivasa T. Reddy, Department of Medicine, and Department of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Drive South, A8-131, CHS, Los Angeles, CA 90095. E-mail sreddy{at}mednet.ucla.edu
Objective— Mitogen-activated protein kinase phosphatase-1 (MKP-1) is one of several oxidized-L-
-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.
Key Words: lipoprotein oxidation • MKP-1 • atherosclerosis • phosphatase inhibitor
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