Glucose-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase-dependent upregulation of the platelet-derived growth factor-β receptor potentiates vascular smooth muscle cell chemotaxis

被引:45
作者
Campbell, M
Allen, WE
Silversides, JA
Trimble, ER
机构
[1] Queens Univ Belfast, Inst Clin Sci, Dept Clin Biochem, Belfast BT12 6BJ, Antrim, North Ireland
[2] Royal Grp Hosp, Belfast, Antrim, North Ireland
关键词
D O I
10.2337/diabetes.52.2.519
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The aim of this study was to investigate the effects of elevated D-glucose concentrations on vascular smooth muscle cell (VSMC) expression of the platelet-derived growth factor (PDGF)p receptor and VSMC migratory behavior. Immunoprecipitation, immunofluorescent staining, and RT-PCR of human VSMCs showed that elevated D-glucose induced an increase in the PDGFbeta receptor that was inhibited by phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathway inhibitors. Exposure to 25 mmol/l D-glucose (HG) induced increased phosphorylation of protein kinase B (PKB) and extracellular-regulated kinase (ERK). All HG chemotaxis assays (with either 10 days' preincubation in HG or no preincubation) in a FCS or PDGF-BB gradient showed positive chemotaxis, whereas those in 5 mmol/l D-glucose did not. Assays were also ran with concentrations ranging from 5 to 25 mmol/l D-glucose. Chemotaxis was induced at concentrations greater than or equal to9 mmol/l D-glucose. An anti-PDGFbeta receptor antibody inhibited glucose-potentiated VSMC chemotaxis, as did the inhibitors for the PI3K and MAPK pathways. This study has shown that small increases in D-glucose concentration, for a short period, increase VSMC expression of the PDGFbeta receptor and VSMC sensitivity to chemotactic factors in serum, leading to altered migratory behavior in vitro. It is probable that similar processes occur in vivo with glucose-enhanced chemotaxis of VSMCs, operating through PDGFbeta receptor-operated pathways, contributing to the accelerated formation of atheroma in diabetes.
引用
收藏
页码:519 / 526
页数:8
相关论文
共 39 条
[1]   Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts [J].
Abordo, EA ;
Westwood, ME ;
Thornalley, PJ .
IMMUNOLOGY LETTERS, 1996, 53 (01) :7-13
[2]   A role for Cdc42 in macrophage chemotaxis [J].
Allen, WE ;
Zicha, D ;
Ridley, AJ ;
Jones, GE .
JOURNAL OF CELL BIOLOGY, 1998, 141 (05) :1147-1157
[3]   Platelet-derived growth factor-BB (PDGF-BB) regulation of migration and focal adhesion kinase phosphorylation in rabbit aortic vascular smooth muscle cells: roles of phosphatidylinositol 3-kinase and mitogen-activated protein kinases [J].
Cospedal, R ;
Abedi, H ;
Zachary, I .
CARDIOVASCULAR RESEARCH, 1999, 41 (03) :708-721
[4]  
Doanes AM, 1998, BIOCHEM MOL BIOL INT, V45, P279
[5]  
DUNN GA, 1995, J CELL SCI, V108, P1239
[6]   CARVEDILOL, A NOVEL MULTIPLE ACTION ANTIHYPERTENSIVE AGENT WITH ANTIOXIDANT ACTIVITY AND THE POTENTIAL FOR MYOCARDIAL AND VASCULAR PROTECTION [J].
FEUERSTEIN, GZ ;
RUFFOLO, RR .
EUROPEAN HEART JOURNAL, 1995, 16 :38-42
[7]  
FRACKELTON AR, 1984, J BIOL CHEM, V259, P7909
[8]   Thrombospondin-1 regulation of smooth muscle cell chemotaxis is extracellular signal-regulated protein kinases 1/2 dependent [J].
Gahtan, V ;
Wang, XJ ;
Willis, AI ;
Tuszynski, GP ;
Sumpio, BE .
SURGERY, 1999, 126 (02) :203-207
[9]   TNF-α-induced migration of vascular smooth muscle cells is MAPK dependent [J].
Goetze, S ;
Xi, XP ;
Kawano, Y ;
Kawano, H ;
Fleck, E ;
Hsueh, WA ;
Law, RE .
HYPERTENSION, 1999, 33 (01) :183-189
[10]   The relationship of glycaemic level to advanced glycation end-product (AGE) accumulation and retinal pathology in the spontaneous diabetic hamster [J].
Hammes, HP ;
Wellensiek, B ;
Klöting, I ;
Sickel, E ;
Bretzel, RG ;
Brownlee, M .
DIABETOLOGIA, 1998, 41 (02) :165-170