IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

2002 ◽  
Vol 283 (3) ◽  
pp. E465-E471 ◽  
Author(s):  
Jennifer L. Hall ◽  
Gary H. Gibbons ◽  
John C. Chatham
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Metabolic Flux ◽  
Tca Cycle ◽  
Muscle Cells ◽  
Glucose Flux ◽  
The Tca Cycle ◽  
Igf I

13C-nuclear magnetic resonance (NMR) spectroscopy was used to test our hypothesis that insulin-like growth factor I (IGF-I) stimulates glucose flux into both nonoxidative and oxidative pathways in vascular smooth muscle cells (VSMC). Rat VSMC were exposed to uniformly labeled [13C]glucose ([U-13C]glucose; 5.5 mM) and [3-13C]pyruvate (1 mM) in the presence and absence of IGF-I (100 ng/ml). IGF-I increased glucose flux through glycolysis and the tricarboxylic acid (TCA) cycle as well as total anaplerotic flux into the TCA cycle. Previous work in our laboratory identified an increase in GLUT1 content and glucose metabolism in neointimal VSMC that was sufficient to promote proliferation and inhibit apoptosis. To test whether IGF-I could potentiate the GLUT1-induced increased flux in the neointima, we utilized VSMC harboring constitutive overexpression of GLUT1. Indeed, IGF-I markedly potentiated the GLUT1-induced increase in glucose flux through glycolysis and the TCA cycle. Taken together, these findings demonstrate that upregulation of glucose transport through either IGF-I or increased GLUT1 content stimulates glucose flux through both nonoxidative and oxidative pathways in VSMC.

scholarly journals IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells

2003 ◽  
Vol 179 (2) ◽  
pp. 267-274 ◽  
Author(s):  
R Jamali ◽  
M Bao ◽  
HJ Arnqvist
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Caspase 3 ◽  
Chromatin Condensation ◽  
Muscle Cells ◽  
Serum Starvation ◽  
Maximal Effect ◽  
Igf I

Apoptosis of vascular smooth muscle cells (VSMCs) is of importance in the development of diabetic angiopathy. Our aim was to evaluate the effect of insulin and IGF-I on apoptosis in VSMCs. Rat aortic VSMCs were used and apoptosis was induced by serum starvation. As apoptotic markers we measured caspase-3 activity, histone-associated DNA fragments by ELISA and nuclear morphology by DAPI (4',6-diamidino-2-phenylindole) staining. Phosphorylation of IGF-I receptors was evaluated by Western blot. Serum starvation had increased caspase-3 activity even after 3 h. The highest activity was found after 3-12 h. IGF-I 10(-9 )M inhibited serum starvation-induced caspase-3 activity with a maximal effect after 12 h. When studied after starvation for 12 h, significant inhibitory effects on caspase-3 were found at IGF-I concentrations of 10(-8)-10(-7) M (P<0.01) and at an insulin concentration of 10(-6 )M (P<0.01). DNA fragmentation was detected by ELISA after 24 h and chromatin condensation and nuclear fragmentation by DAPI staining after 24 and 48 h respectively. IGF-I dose-dependently reduced apoptosis evaluated by ELISA, reaching a maximal effect at 10(-9) M. Insulin reduced apoptosis but the effect was weaker and a higher concentration was needed. IGF-I (10(-8 )M) and insulin at a very high concentration (10(-6) M) phosphorylated IGF-I receptors. Taken together, IGF-I and insulin have antiapoptotic effects on VSMCs but the effect of insulin is only found at high unphysiological concentration.

Interaction of angiotensin II and the insulin-like growth factor system in vascular smooth muscle cells

1999 ◽  
Vol 277 (2) ◽  
pp. H499-H507 ◽  
Author(s):  
Thomas Gustafsson ◽  
Peter Andersson ◽  
Yun Chen ◽  
Jan Olof Magnusson ◽  
Hans J. Arnqvist
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Dna Synthesis ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Igf I

We studied the effects and interactions of ANG II and the insulin-like growth factor (IGF) system in cultured rat aortic smooth muscle cells. ANG II (1 μM) and IGF-I (10 nM) stimulated both DNA and protein synthesis. The effects of the two peptides in combination were additive or more than additive. The AT1 receptor antagonist losartan (10 and 100 μM) blocked their synergistic effect on DNA synthesis. IGF binding protein (IGFBP)-1 inhibited the effect of IGF-I but not that of ANG II on DNA synthesis. IGF-I stimulated gene expression of IGFBP-2 and IGFBP-4. ANG II decreased IGF-I, IGFBP-2, and IGFBP-4 transcripts but increased the IGF-I receptor transcript. IGF-I and ANG II in combination had similar effects on gene expression as ANG II alone. The IGFBP-2 and IGFBP-4 peptides could be detected in the conditioned medium. Our results show that ANG II and IGF-I have synergistic effects on vascular smooth muscle cells and that they interact in several ways.

scholarly journals Suppression of AMPK Activation via S485 Phosphorylation by IGF-I during Hyperglycemia Is Mediated by AKT Activation in Vascular Smooth Muscle Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3143-3154 ◽  
Author(s):  
Junyu Ning ◽  
Gang Xi ◽  
David R. Clemmons
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Glucose ◽  
Muscle Cells ◽  
Igf I ◽  
Ampk Activity

As a metabolic sensor, the serine/threonine protein kinase AMP-activated protein kinase (AMPK) promotes the adaptation of cells to signals arising from nutrients, hormones, and growth factors. The ability of IGF-I to stimulate protein synthesis is suppressed by AMPK, therefore, these studies were undertaken to determine whether IGF-I modulates AMPK activity. IGF-I dose-dependently suppressed phosphorylation of AMPK T172, and it stimulated AMPK S485 phosphorylation in vascular smooth muscle cells (VSMC). To determine whether stimulation of AMPK S485 phosphorylation was mediating this response, VSMC were transduced with a mutant AMPKα (AMPK S485A). Expression of this altered form inhibited the ability of IGF-I to suppress AMPK T172 activation, which resulted in inhibition of IGF-I-stimulated phosphorylation of P70S6 kinase. In contrast, expression of an AMPK S485D mutant resulted in constitutive suppression of AMPK activity and was associated with increased IGF-I-stimulated P70S6K phosphorylation and protein synthesis. The addition of a specific AKT inhibitor or expression of an AKT1 short hairpin RNA inhibited AMPK S485 phosphorylation, and it attenuated the IGF-I-induced decrease in AMPK T172 phosphorylation. Exposure to high glucose concentrations suppressed AMPK activity and stimulated S485 phosphorylation, and IGF-I stimulated a further increase in S485 phosphorylation and AMPK T172 suppression. We conclude that AMPK S485 phosphorylation negatively regulates AMPK activity by modulating the T172 phosphorylation response to high glucose and IGF-I. IGF-I stimulates S485 phosphorylation through AKT1. The results suggest that AMPK plays an inhibitory role in modulating IGF-I-stimulated protein synthesis and that IGF-I must down-regulate AMPK activity to induce an optimal anabolic response.

Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells

1997 ◽  
Vol 135 (2) ◽  
pp. 213-223 ◽  
Author(s):  
José Martı́nez-González ◽  
Marisa Viñals ◽  
Francisco Vidal ◽  
Vicenta Llorente-Cortés ◽  
Lina Badimon
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Insulin Signaling ◽  
Muscle Cells ◽  
Igf I

scholarly journals Aldosterone Enhances IGF-I-Mediated Signaling and Biological Function in Vascular Smooth Muscle Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5851-5864 ◽  
Author(s):  
Teresa Cascella ◽  
Yashwanth Radhakrishnan ◽  
Laura A. Maile ◽  
Walker H. Busby ◽  
Katherine Gollahon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Synergistic Effects ◽  
Fold Increase ◽  
Muscle Cells ◽  
Αvβ3 Integrin ◽  
Vsmc Proliferation ◽  
Igf I

The IGF-I pathway and renin-angiotensin-aldosterone axis are both involved in the pathogenesis of hypertension and atherosclerosis, but no information is available about IGF-I and aldosterone interaction or their potential synergistic effects in vascular smooth muscle cells (VSMCs). The aims of this study were to investigate whether aldosterone influences IGF-I signaling and to determine the mechanism(s) by which aldosterone affects IGF-I function. Aldosterone resulted in significant increases in the Akt (1.87 ± 0.24, P &lt; 0.001), MAPK (1.78 ± 0.13, P &lt; 0.001), p70S6kinase (1.92 ± 0.15, P &lt; 0.001), IGF-I receptor (1.69 ± 0.05, P &lt; 0.01), and insulin receptor substrate-1 (1.7 ± 0.04, P &lt; 0.01) (fold increase, mean ± SEM, n = 3) phosphorylation responses to IGF-I compared with IGF-I treatment alone. There were also significant increases in VSMC proliferation, migration, and protein synthesis (1.63 ± 0.03-, 1.56 ± 0.08-, and 1.51 ± 0.04-fold increases compared with IGF-I alone, respectively, n = 3, P &lt; 0.001). Aldosterone induced osteopontin (OPN) mRNA expression and activation of αVβ3-integrin as well as an increase in the synthesis of IGF-I receptor. The enhancing effects of aldosterone were inhibited by eplerenone (10 μmol/liter), actinomycin-D (20 nmol/liter), and an anti-αVβ3-integrin antibody that blocks OPN binding. The antioxidant N-acetylcysteine (2 mmol/liter) completely inhibited the ability of aldosterone to induce any of these changes. In conclusion, our results show that aldosterone enhances IGF-I signaling and biological actions in VSMCs through induction of OPN followed by its subsequent activation of the αVβ3-integrin and by increasing IGF-I receptor. These changes are mediated in part through increased oxidative stress. The findings suggest a new mechanism by which aldosterone could accelerate the development of atherosclerosis.

scholarly journals Different inhibitory actions of IGFBP-1, -2 and -4 on IGF-I effects in vascular smooth muscle cells

1999 ◽  
Vol 161 (2) ◽  
pp. 245-253 ◽  
Author(s):  
T Gustafsson ◽  
P Andersson ◽  
HJ Arnqvist
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Dna Synthesis ◽  
Conditioned Medium ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Igf I ◽  
Dna And Protein Synthesis

IGF-I is involved in the regulation of metabolism, growth and migration of vascular smooth muscle cells (VSMCs). We have studied how IGFBP-1, -2 and -4 modulate IGF-I-induced DNA and protein synthesis in cultured rat VSMCs. DNA and protein synthesis were measured as incorporation of [3H]thymidine and [3H]leucine into DNA and protein respectively. Western immunoblot was used to detect IGFBPs in conditioned medium and solution hybridization was used to measure IGFBP gene expression. IGF-I stimulated DNA synthesis with an EC50 of 44 pM, reaching a maximal effect at 1 nM. An IGF-I concentration of 1 nM was subsequently used in the experiments with IGFBPs. IGFBP-1 and IGFBP-4 acted in an inhibitory manner on IGF-I-induced DNA synthesis with calculated IC50 values of 1.6 nM and 6.2 nM respectively. IGFBP-2 (16 nM) also inhibited the growth response to IGF-I, but this effect could only be obtained if the two peptides were pre-incubated together for 2 h prior to addition to the cells. IGFBP-1, -2 and -4 inhibited IGF-I-induced protein synthesis in a similar way. Immunoblot of the incubation medium showed little degradation of IGFBP-2 and -4 for up to 24 h. mRNA for IGFBP-2 and -4, but not for IGFBP-1 was detected in the VSMCs. Endogenous IGFBP-2 and -4 could be detected by immunoblot in the conditioned medium but only if it was concentrated. In conclusion, IGFBP-1, -2 and -4, of which IGFBP-2 and -4 may be locally derived, act as inhibitors with different potencies on IGF-I effects in VSMCs.

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