This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 95/4/380    most recent 01.RES.0000138019.82184.5dv2 01.RES.0000138019.82184.5dv1 Alert me when this article is cited 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 Campbell, M. Articles by Trimble, E. R. Search for Related Content PubMed PubMed Citation Articles by Campbell, M. Articles by Trimble, E. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE LOVASTATIN Related Collections Cell signalling/signal transduction Type 2 diabetes Mechanism of atherosclerosis/growth factors

Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways

From the Department of Clinical Biochemistry and Metabolic Medicine (M.C., W.E.A., E.R.T.), Queen’s University Belfast, Institute of Clinical Science, Royal Victoria Hospital, Belfast; and Ludwig Institute for Cancer Research (C.S., B.V.), London, UK.

Correspondence to Prof E.R. Trimble, MD, Department of Clinical Biochemistry and Metabolic Medicine, Queen’s University Belfast, Institute of Clinical Science, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BJ, UK. E-mail e.trimble{at}qub.ac.uk

Atheroma formation involves the movement of vascular smooth muscle cells (VSMC) into the subendothelial space. The aim of this study was to determine the involvement of PI3K and MAPK pathways and the importance of cross-talk between these pathways, in glucose-potentiated VSMC chemotaxis to serum factors. VSMC chemotaxis occurred in a serum gradient in 25 mmol/L glucose (but not in 5 mmol/L glucose) in association with increased phosphorylation (activation) of Akt and ERK1/2 in PI3K and MAPK pathways, respectively. Inhibitors of these pathways blocked chemotaxis, as did an mTOR inhibitor. VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110ß isoform was involved in chemotaxis. ERK1/2 phosphorylation was reduced not only by MAPK pathway inhibitors but also by PI3K and mTOR inhibitors; when PI3K was inhibited, ERK phosphorylation could be induced by microinjected activated Akt, indicating important cross-talk between the PI3K and ERK1/2 pathways. Glucose-potentiated phosphorylation of molecules in the p38 and JNK MAPK pathways inhibited these pathways but did not affect chemotaxis. The statin, mevinolin, blocked chemotaxis through its effects on the MAPK pathway. Mevinolin-inhibited chemotaxis was restored by farnesylpyrophosphate but not by geranylgeranylpyrophosphate; in the absence of mevinolin, inhibition of farnesyltransferase reduced ERK phosphorylation and blocked chemotaxis, indicating a role for the Ras family of GTPases (MAPK pathway) under these conditions. In conclusion, glucose sensitizes VSMC to serum, inducing chemotaxis via pathways involving p110ß-PI3K, Akt, mTOR, and ERK1/2 MAPK. Cross-talk between the PI3K and MAPK pathways is necessary for VSMC chemotaxis under these conditions.

Key Words: diabetes • atherosclerosis • Akt • ERK • statin

This article has been cited by other articles:

				B. Zheng, M. Han, M. Bernier, X.-h. Zhang, F. Meng, S.-b. Miao, M. He, X.-m. Zhao, and J.-k. Wen Kruppel-like Factor 4 Inhibits Proliferation by Platelet-derived Growth Factor Receptor {beta}-mediated, Not by Retinoic Acid Receptor {alpha}-mediated, Phosphatidylinositol 3-Kinase and ERK Signaling in Vascular Smooth Muscle Cells J. Biol. Chem., August 21, 2009; 284(34): 22773 - 22785. [Abstract] [Full Text] [PDF]

				H. Kinoshita, N. Matsuda, H. Kaba, N. Hatakeyama, T. Azma, K. Nakahata, Y. Kuroda, K. Tange, H. Iranami, and Y. Hatano Roles of Phosphatidylinositol 3-Kinase-Akt and NADPH Oxidase in Adenosine 5'-Triphosphate-Sensitive K+ Channel Function Impaired by High Glucose in the Human Artery Hypertension, September 1, 2008; 52(3): 507 - 513. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, E. C. Miller, L. B. Allen, U. Veluvolu, A. W. Aday, and D. R. Clemmons Glucose Regulation of Integrin-Associated Protein Cleavage Controls the Response of Vascular Smooth Muscle Cells to Insulin-Like Growth Factor-I Mol. Endocrinol., May 1, 2008; 22(5): 1226 - 1237. [Abstract] [Full Text] [PDF]

				N. J. MacLaine, M. D. Wood, J. C. Holder, R. W. Rees, and J. Southgate Sensitivity of Normal, Paramalignant, and Malignant Human Urothelial Cells to Inhibitors of the Epidermal Growth Factor Receptor Signaling Pathway Mol. Cancer Res., January 1, 2008; 6(1): 53 - 63. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, Y. Ling, G. Xi, and D. R. Clemmons Hyperglycemia Alters the Responsiveness of Smooth Muscle Cells to Insulin-Like Growth Factor-I Endocrinology, May 1, 2007; 148(5): 2435 - 2443. [Abstract] [Full Text] [PDF]

				S. Han, J. D. Ritzenthaler, B. Wingerd, H. N. Rivera, and J. Roman Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways: THE ROLE OF AP-2 J. Biol. Chem., March 16, 2007; 282(11): 7961 - 7972. [Abstract] [Full Text] [PDF]

				C. Lopez-Lopez, M. O. Dietrich, F. Metzger, H. Loetscher, and I. Torres-Aleman Disturbed Cross Talk between Insulin-Like Growth Factor I and AMP-Activated Protein Kinase as a Possible Cause of Vascular Dysfunction in the Amyloid Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease J. Neurosci., January 24, 2007; 27(4): 824 - 831. [Abstract] [Full Text] [PDF]

				V. S. Mahadevan, M. Campbell, P. P. McKeown, and U. Bayraktutan Internal mammary artery smooth muscle cells resist migration and possess high antioxidant capacity Cardiovasc Res, October 1, 2006; 72(1): 60 - 68. [Abstract] [Full Text] [PDF]

				W. G. Tharp, R. Yadav, D. Irimia, A. Upadhyaya, A. Samadani, O. Hurtado, S-Y. Liu, S. Munisamy, D. M. Brainard, M. J. Mahon, et al. Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo J. Leukoc. Biol., March 1, 2006; 79(3): 539 - 554. [Abstract] [Full Text] [PDF]

				H. Hayashi, O. Matsuzaki, S. Muramatsu, Y. Tsuchiya, T. Harada, Y. Suzuki, S. Sugano, A. Matsuda, and E. Nishida Centaurin-{alpha}1 Is a Phosphatidylinositol 3-Kinase-dependent Activator of ERK1/2 Mitogen-activated Protein Kinases J. Biol. Chem., January 20, 2006; 281(3): 1332 - 1337. [Abstract] [Full Text] [PDF]

				H. He, H.-T. Cho, W. Li, T. Kawakita, L. Jong, and S. C. G. Tseng Signaling-Transduction Pathways Required for Ex Vivo Expansion of Human Limbal Explants on Intact Amniotic Membrane Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 151 - 157. [Abstract] [Full Text] [PDF]

				Z. T. Kneass and R. B. Marchase Protein O-GlcNAc Modulates Motility-associated Signaling Intermediates in Neutrophils J. Biol. Chem., April 15, 2005; 280(15): 14579 - 14585. [Abstract] [Full Text] [PDF]

				M. Campbell and E. R. Trimble Modification of PI3K- and MAPK-Dependent Chemotaxis in Aortic Vascular Smooth Muscle Cells by Protein Kinase C{beta}II Circ. Res., February 4, 2005; 96(2): 197 - 206. [Abstract] [Full Text] [PDF]