This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Metzler, B. Articles by Xu, Q. Search for Related Content PubMed PubMed Citation Articles by Metzler, B. Articles by Xu, Q. Related Collections Physiological and pathological control of gene expression Smooth muscle proliferation and differentiation Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1862-1871.)
© 1999 American Heart Association, Inc.

Vascular Biology

LDL Stimulates Mitogen-Activated Protein Kinase Phosphatase-1 Expression, Independent of LDL Receptors, in Vascular Smooth Muscle Cells

Bernhard Metzler; Chaohong Li; Yanhua Hu; Gertraud Sturm; Nassim Ghaffari-Tabrizi; Qingbo Xu

From the Institute for Biomedical Aging Research (B.M., C.L., Y.H., G.S., Q.X.), Austrian Academy of Sciences, and the Division of Cardiology (B.M.), Department of Internal Medicine, University Hospital of Innsbruck, and the Institute for Medical Biology and Human Genetics (N.G.-T.), University of Innsbruck Medical School, Innsbruck, Austria.

Correspondence to Dr Qingbo Xu, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail qingbo.xu{at}oeaw.ac.at

Abstract—Low density lipoprotein (LDL) is a well-established risk factor for atherosclerosis, stimulating vascular smooth muscle cell (SMC) differentiation and proliferation, but the signal transduction pathways between LDL stimulation and cell proliferation are poorly understood. Because mitogen-activated protein kinases (MAPKs) play a crucial role in mediating cell growth, we studied the effect of LDL on the induction of MAPK phosphatase-1 (MKP-1) in human SMCs and found that LDL stimulated induction of MKP-1 mRNA and proteins in a time- and dose-dependent manner. Heparin, inhibiting LDL-receptor binding, did not influence LDL-stimulated MKP-1 mRNA expression, and human LDL also induced MKP-1 expression in rat SMCs and fibroblasts derived from LDL receptor–deficient mice, indicating an LDL receptor–independent process. Pretreatment of SMCs with pertussis toxin markedly inhibited LDL-induced MKP-1 expression. Depletion of protein kinase C (PKC) by phorbol 12-myristate 13 acetate or inhibition of PKC by calphostin C blocked MKP-1 induction, but the phospholipase C inhibitor U73122 had no effect. Pretreatment of SMCs with genistein or herbimycin A abrogated LDL-stimulated MKP-1 induction. The MAPK kinase inhibitor PD98059 abolished LDL-stimulated activation of extracellular signal–regulated protein kinases (ERKs) but not MKP-1 induction. Furthermore, constitutive expression of MKP-1 in vivo reduced LDL-induced expression of Elk-1–dependent reporter genes, and SMC lines overexpressing recombinant MKP-1 exhibited decreased ERK activities and retarded proliferation in response to LDL. Our findings demonstrate that LDL induces MKP-1 expression in SMCs via activation of PKC and tyrosine kinases, independent of LDL receptors and ERK-MAPKs, and that MKP-1 plays an important role in the regulation of LDL-initiated signal transductions leading to SMC proliferation.

Key Words: LDL • mitogen-activated protein kinase phosphatase-1 • signaling • mitogen-activated protein kinases • smooth muscle cells

This article has been cited by other articles:

				U. M. Chandrasekharan, L. Yang, A. Walters, P. Howe, and P. E. DiCorleto Role of CL-100, a Dual Specificity Phosphatase, in Thrombin-induced Endothelial Cell Activation J. Biol. Chem., November 5, 2004; 279(45): 46678 - 46685. [Abstract] [Full Text] [PDF]

				A.-Y. Tu, M. C. Cheung, X. Zhu, R. H. Knopp, and J. J. Albers Low-Density Lipoprotein Inhibits Secretion of Phospholipid Transfer Protein in Human Trophoblastic BeWo Cells Experimental Biology and Medicine, November 1, 2004; 229(10): 1046 - 1052. [Abstract] [Full Text] [PDF]

				P. Robin, I. Boulven, C. Bole-Feysot, Z. Tanfin, and D. Leiber Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells Am J Physiol Cell Physiol, April 1, 2004; 286(4): C798 - C806. [Abstract] [Full Text] [PDF]

				S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]

				Q. Xu, Z. Zhang, F. Davison, and Y. Hu Circulating Progenitor Cells Regenerate Endothelium of Vein Graft Atherosclerosis, Which Is Diminished in ApoE-Deficient Mice Circ. Res., October 17, 2003; 93 (8): e76 - e86. [Abstract] [Full Text] [PDF]

				Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]

				R. Locher, R. P. Brandes, W. Vetter, and M. Barton Native LDL Induces Proliferation of Human Vascular Smooth Muscle Cells via Redox-Mediated Activation of ERK 1/2 Mitogen-Activated Protein Kinases Hypertension, February 1, 2002; 39(2): 645 - 650. [Abstract] [Full Text] [PDF]

				Y. Zhu, H. Liao, N. Wang, K.-S. Ma, L. K. Verna, J. Y.-J. Shyy, S. Chien, and M. B. Stemerman LDL-Activated p38 in Endothelial Cells Is Mediated by Ras Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1159 - 1164. [Abstract] [Full Text] [PDF]

				H. Dietrich, Y. Hu, Y. Zou, U. Huemer, B. Metzler, C. Li, M. Mayr, and Q. Xu Rapid Development of Vein Graft Atheroma in ApoE-Deficient Mice Am. J. Pathol., August 1, 2000; 157(2): 659 - 669. [Abstract] [Full Text] [PDF]

				B. Metzler, Y. Hu, H. Dietrich, and Q. Xu Increased Expression and Activation of Stress-Activated Protein Kinases/c-Jun NH2-Terminal Protein Kinases in Atherosclerotic Lesions Coincide with p53 Am. J. Pathol., June 1, 2000; 156(6): 1875 - 1886. [Abstract] [Full Text] [PDF]

				C. Li, Y. Hu, G. Sturm, G. Wick, and Q. Xu Ras/Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinases in Smooth Muscle Cells Stimulated by Cyclic Strain Stress Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20 (3): e1 - e9. [Abstract] [Full Text] [PDF]

				M. MAYR, C. LI, Y. ZOU, U. HUEMER, Y. HU, and Q. XU Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases FASEB J, February 1, 2000; 14(2): 261 - 270. [Abstract] [Full Text]

				S. Reddy, S. Hama, V. Grijalva, K. Hassan, R. Mottahedeh, G. Hough, D. J. Wadleigh, M. Navab, and A. M. Fogelman Mitogen-activated Protein Kinase Phosphatase 1 Activity Is Necessary for Oxidized Phospholipids to Induce Monocyte Chemotactic Activity in Human Aortic Endothelial Cells J. Biol. Chem., May 11, 2001; 276(20): 17030 - 17035. [Abstract] [Full Text] [PDF]