Potential role for mitogen-activated protein kinase phosphatase-1 in the development of atherosclerotic lesions in mouse models.
OBJECTIVE
Mitogen-activated protein kinase phosphatase-1 (MKP-1) is one of several oxidized-l-alpha-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.


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.


CONCLUSIONS
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.
Reddy
Srinivasa T
ST
Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, University of California Los Angeles, 650 Charles E. Young Drive South, A8-131, CHS, Los Angeles, CA 90095, USA. sreddy@mednet.ucla.edu
Nguyen
Julie T
JT
Grijalva
Victor
V
Hough
Greg
G
Hama
Susan
S
Navab
Mohamad
M
Fogelman
Alan M
AM
D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001018:Aortic Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000201:enzymology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004036:Diet, Atherogenic; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D004790:Enzyme Induction / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D023421:Models, Animal; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012737:Sex Factors; D014638:Vanadates / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D018797:Cell Cycle Proteins; D004134:Dimyristoylphosphatidylcholine; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D012333:RNA, Messenger; D011973:Receptors, LDL; D014638:Vanadates; D048051:p38 Mitogen-Activated Protein Kinases; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C517019:DUSP1 protein, human; C517020:Dusp1 protein, mouse