Published online before print December 9, 2004, doi: 10.1161/01.RES.0000152966.88353.9d
© 2005 American Heart Association, Inc.
Cellular Biology |
Modification of PI3K- and MAPK-Dependent Chemotaxis in Aortic Vascular Smooth Muscle Cells by Protein Kinase CßII
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 PKCßII levels were increased in 25 mmol/L glucose. However, only PKCßII 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 PKCßII 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 PKCßII inhibition. Formation of lamellipodia was dependent on PI3K activation and filopodia on MAPK activation; both lamellipodia and filopodia were eliminated when PKCßII 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 PKCßII-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
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