Gene interactions and pathways from curated databases and text-mining
Diabetologia 2006, PMID: 16506055

Insulin activates hypoxia-inducible factor-1alpha 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.

Doronzo, G; Russo, I; Mattiello, L; Riganti, C; Anfossi, G; Trovati, M

OBJECTIVE

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-1alpha 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-1alpha 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-1alpha 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-1alpha 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

These results provide a biological mechanism for the impaired collateral vessel formation in obesity.

Diseases/Pathways annotated by Medline MESH: Insulin Resistance
Document information provided by NCBI PubMed

Text Mining Data

VEGF → hypoxia-inducible factor-1 (HIF-1): " 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-1alpha protein synthesis and activity ; ( 2 ) the insulin signalling pathways involved ; and ( 3 ) the role of insulin resistance "

VEGF — insulin: " 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-1alpha protein synthesis and activity ; ( 2 ) the insulin signalling pathways involved ; and ( 3 ) the role of insulin resistance "

hypoxia-inducible factor-1 (HIF-1) — insulin: " 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-1alpha protein synthesis and activity ; ( 2 ) the insulin signalling pathways involved ; and ( 3 ) the role of insulin resistance "

HIF-1 — insulin: " 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-1alpha 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 "

HIF-1alpha → insulin: " The insulin induced increase of HIF-1alpha is blunted by the translation inhibitor cycloheximide, LY294002, PD98059, SP600125 and rapamycin, but not by SB203580 "

ERK-1/2 → insulin: " 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 "

Akt → insulin: " 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 "

ERK-1/2 → insulin: " 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 "

ERK-1/2 → insulin: " 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 "

Manually curated Databases

No curated data.