Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways:: impairment in insulin resistance owing to defects in insulin signalling

被引:37
|
作者
Doronzo, G
Russo, I
Matticello, L
Riganti, C
Anfossi, G
Trovati, M [1 ]
机构
[1] Univ Turin, San Luigi Gonzaga Hosp, Dept Clin & Biol Sci, Diabet Unit, I-10043 Turin, Italy
[2] Univ Turin, Dept Genet Biol & Med Chem, I-10043 Turin, Italy
关键词
c-Jun N-terminal kinase; hypoxia-inducible factor; insulin; insulin resistance; mitogen-activated protein kinase; obesity; phosphatidylinositol-3; kinase; vascular endothelial growth factor; vascular smooth muscle; Zucker rats;
D O I
10.1007/s00125-006-0156-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims/hypothesis: We previously demonstrated that insulin stimulates vascular endothelial growth factor (VEGF) synthesis and secretion via phosphatidylinositol-3 kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways in vascular smooth muscle cells (VSMC) from humans and from insulin-sensitive lean Zucker fa/+ rats. We also showed that this effect is attenuated in VSMC from insulin-resistant obese Zucker fa/fa rats. As it is not known whether the effects of insulin on VEGF involve activation of hypoxia-inducible factor-1 (HIF-1), we aimed to evaluate: (1) whether insulin modulates HIF-1 alpha protein synthesis and activity; (2) the insulin signalling pathways involved; and (3) the role of insulin resistance. Methods: Using aortic VSMC taken from humans and Zucker rats and cultured in normoxia, the following were evaluated: (1) dose-dependent (0.5, 1, 2 nmol/l) and time-dependent (2, 4, 6 h) effects exerted by insulin on HIF-1 alpha content in both nucleus and cytosol, measured by Western blots; (2) insulin effects on HIF-1 DNA-binding activity on the VEGF gene, measured by electrophoretic mobility shift assay; and (3) involvement of the insulin signalling molecules in these insulin actions, by using the following inhibitors: LY294002 (PI3-K), PD98059 (extracellular signal regulated kinase [ERK]), SP600125 (Jun N terminal kinase [JNK]), SB203580 (p38 mitogen-activated protein kinase) and rapamycin (mammalian target of rapamycin), and by detecting the insulin signalling molecules by Western blots. Results: In aortic VSMC from humans and Zucker fa/+ rats cultured in normoxia insulin increases the HIF-1 alpha content in cytosol and nucleus via dose- and time-dependent mechanisms, and HIF-1 DNA-binding activity on the VEGF gene. The insulin-induced increase of HIF-1 alpha is blunted by the translation inhibitor cycloheximide, LY294002, PD98059, SP600125 and rapamycin, but not by SB203580. It is also reduced in Zucker fa/fa rats,which present an impaired ability of insulin to induce Akt, ERK-1/2 and JNK-1/2 phosphorylation. Conclusions/interpretation: These results provide a biological mechanism for the impaired collateral vessel formation in obesity.
引用
收藏
页码:1049 / 1063
页数:15
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