This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 96/2/197    most recent 01.RES.0000152966.88353.9dv1 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 D-SORBITOL GLUCOSE Related Collections Pathophysiology Cell signalling/signal transduction Growth factors/cytokines Other diabetes Mechanism of atherosclerosis/growth factors

Modification of PI3K- and MAPK-Dependent Chemotaxis in Aortic Vascular Smooth Muscle Cells by Protein Kinase C_ßII

From the Department of Clinical Biochemistry and Metabolic Medicine, Queen’s University Belfast, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK; and Department of Clinical Biochemistry, The Royal Group of Hospitals, Belfast, UK.

Correspondence to Malcolm Campbell, Queen’s University Belfast, Institute of Clinical Science, Royal Victoria Hospital, Grosvenor Rd, Belfast BT12 6BJ, UK. E-mail malcolm.campbell{at}qub.ac.uk

Hyperglycemia increases expression of platelet-derived growth factor (PDGF)-ß receptor and potentiates chemotaxis to PDGF-BB in human aortic vascular smooth muscle cells (VSMCs) via PI3K and ERK/MAPK signaling pathways. The purpose of this study was to determine whether increased activation of protein kinase C (PKC) isoforms had a modulatory effect on the PI3K and ERK/MAPK pathways, control of cell adhesiveness, and movement. All known PKC isoforms were assessed but only PKC and PKC_ßII levels were increased in 25 mmol/L glucose. However, only PKC_ßII inhibition affected (decreased) PI3K pathway and MAPK pathway activities and inhibited PDGF-ß receptor upregulation in raised glucose, and specific MAPK inhibition was required to completely block the effect of glucose. In raised glucose conditions, activity of the ERK/MAPK pathway, PI3K pathway, and PKC_ßII were all sensitive to aldose reductase inhibition. Chemotaxis to PDGF-BB (360 pmol/L), absent in 5 mmol/L glucose, was present in raised glucose and could be blocked by PKC_ßII inhibition. Formation of lamellipodia was dependent on PI3K activation and filopodia on MAPK activation; both lamellipodia and filopodia were eliminated when PKC_ßII was inhibited. FAK phosphorylation and cell adhesion were reduced by PI3K inhibition, and although MAPK inhibition prevented chemotaxis, it did not affect FAK phosphorylation or cell adhesiveness. In conclusion, chemotaxis to PDGF-BB in 25 mmol/L glucose is PKC_ßII-dependent and requires activation of both the PI3K and MAPK pathways. Changes in cell adhesion and migration speed are mediated mainly through the PI3K pathway.

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

This article has been cited by other articles:

				D. R. D'Souza, M. M. Salib, J. Bennett, M. Mochin-Peters, K. Asrani, S. E. Goldblum, K. J. Renoud, P. Shapiro, and A. Passaniti Hyperglycemia Regulates RUNX2 Activation and Cellular Wound Healing through the Aldose Reductase Polyol Pathway J. Biol. Chem., July 3, 2009; 284(27): 17947 - 17955. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, E. C. Miller, A. W. Aday, and D. R. Clemmons Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo Diabetes, October 1, 2008; 57(10): 2637 - 2643. [Abstract] [Full Text] [PDF]

				Y. Radhakrishnan, L. A. Maile, Y. Ling, L. M. Graves, and D. R. Clemmons Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells J. Biol. Chem., June 13, 2008; 283(24): 16320 - 16331. [Abstract] [Full Text] [PDF]

				W. T. Gerthoffer Migration of Airway Smooth Muscle Cells Proceedings of the ATS, January 1, 2008; 5(1): 97 - 105. [Abstract] [Full Text] [PDF]

				W. T. Gerthoffer Mechanisms of Vascular Smooth Muscle Cell Migration Circ. Res., March 16, 2007; 100(5): 607 - 621. [Abstract] [Full Text] [PDF]

				K. V. Ramana, M. S. Willis, M. D. White, J. W. Horton, J. M. DiMaio, D. Srivastava, A. Bhatnagar, and S. K. Srivastava Endotoxin-Induced Cardiomyopathy and Systemic Inflammation in Mice Is Prevented by Aldose Reductase Inhibition Circulation, October 24, 2006; 114(17): 1838 - 1846. [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]

				M. C. Mendonca, S. Q. Doi, S. Glerum, and D. F. Sellitti Increase of C-Type Natriuretic Peptide Expression by Serum and Platelet-Derived Growth Factor-BB in Human Aortic Smooth Muscle Cells Is Dependent on Protein Kinase C Activation Endocrinology, September 1, 2006; 147(9): 4169 - 4178. [Abstract] [Full Text] [PDF]

				S. Gayral, P. Deleris, K. Laulagnier, M. Laffargue, J.-P. Salles, B. Perret, M. Record, and M. Breton-Douillon Selective Activation of Nuclear Phospholipase D-1 by G Protein-Coupled Receptor Agonists in Vascular Smooth Muscle Cells Circ. Res., July 21, 2006; 99(2): 132 - 139. [Abstract] [Full Text] [PDF]

				R. M. Day, Y. H. Lee, A.-M. Park, and Y. J. Suzuki Retinoic Acid Inhibits Airway Smooth Muscle Cell Migration Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 695 - 703. [Abstract] [Full Text] [PDF]

				S. Srivastava, K. V. Ramana, R. Tammali, S. K. Srivastava, and A. Bhatnagar Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells. Diabetes, April 1, 2006; 55(4): 901 - 910. [Abstract] [Full Text] [PDF]

				L. Ragolia, T. Palaia, C. E. Hall, J. K. Maesaka, N. Eguchi, and Y. Urade Accelerated Glucose Intolerance, Nephropathy, and Atherosclerosis in Prostaglandin D2 Synthase Knock-out Mice J. Biol. Chem., August 19, 2005; 280(33): 29946 - 29955. [Abstract] [Full Text] [PDF]