Insulin-Like Growth Factor-1 Receptor Expression Masks the Antiinflammatory and Glucose Uptake Capacity of Insulin in Vascular Smooth Muscle Cells

Engberding, Niels; Martín, Alejandra San; Martín-Garrido, Abel; Koga, Mitsuhisa; Pounkova, Lily; Lyons, Erin; Lassègue, Bernard; Griendling, Kathy K.

doi:10.1161/atvbaha.108.181727

Cited by 42 publications

(43 citation statements)

References 54 publications

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“…In accordance with our proposed mechanism for insulin resistance in human VSMCs (Fig. 8), disruption of IGF1R in breast cancer cells, osteoblast, and rat VSMC is followed by an increased fraction of insulin holoreceptors and reduced insulin resistance (Fulzele et al 2007, Zhang et al 2007, Engberding et al 2009). …”

supporting

confidence: 87%

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Chisalita¹,

Johansson²,

Liefvendahl³

et al. 2009

Journal of Molecular Endocrinology

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Whether insulin, at physiological concentrations, has direct effects on vascular smooth muscle cells (VSMCs) remains controversial. Our aim was to characterize the mechanism for insulin resistance in VSMCs. For comparison, the effects of IGF1 and IGF2 were also studied. Cultured human aortic smooth muscle cells (HASMC) were used. Receptor mRNA was analyzed by quantitative reverse transcription PCR and receptor protein by ELISA and western blot. Biological effects were studied by thymidine incorporation and glucose accumulation. In HASMC, both mRNA and protein expression of IGF1 receptors (IGF1R) were fivefold higher compared to insulin receptor (IR). IR isoform A mRNA was 13-fold more expressed than IR isoform B. IR and IGF1R co-precipitated, indicating the presence of hybrid IR/IGF1R. Phosphorylation of the IGF1R b-subunit was obtained by IGF1 10 K9

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supporting

confidence: 87%

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Chisalita¹,

Johansson²,

Liefvendahl³

et al. 2009

Journal of Molecular Endocrinology

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“…37 Recently, Cascella et al 38 reported that aldosterone accelerates the development of atherosclerosis via IGF1-mediated signaling in VSMCs. In addition, Engberding et al 9 reported that aortas of diabetic mice expressed significantly more IGF1R in all wall layers than did those of age-matched controls. However, it is methodologically difficult to distinguish the effects of IGF1R and IR, because both receptors partly share a common downstream signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Protein samples from VSMCs or aorta (600 g of protein) were immunoprecipitated by overnight incubation with anti-IR␤-subunit antibody, followed by immunoblot analysis with an antibody against IGF1R␤-subunit. 8,9 Real-Time Reverse Transcription-Polymerase Chain Reaction…”

Section: Western Blot Analysis and Immunoprecipitationmentioning

confidence: 99%

“…8 Compared with IR, IGF1R is more abundant in VSMCs, and expression of IGF1R is increased in aortas of diabetic animals. 9 Furthermore, subunits of IR and IGF1R easily form hybrid receptors, depending on the ratio of these receptors' expressions. 10 These hybrid receptors function more like IGF1R in that they have higher affinity for insulin-like growth factor-1 (IGF1) than to insulin.…”

mentioning

confidence: 99%

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Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor

Sherajee

Fujita

Rafiq

et al. 2012

ATVB

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Objective-We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs).Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. Methods and Results-Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by 3 H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and ␣-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 g/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. Key Words: insulin resistance Ⅲ reactive oxygen species Ⅲ receptors Ⅲ signal transduction Ⅲ aldosterone I nsulin resistance is a major attribute of type 2 diabetes mellitus and metabolic syndrome. 1 Cardiovascular complications are often seen in these patients, and vascular insulin resistance is considered to be involved in proatherogenic changes and subsequent cardiovascular events. 2 There is growing interest in the role of aldosterone and its receptor, mineralocorticoid receptor (MR), in the pathogenesis of insulin resistance. 3 For instance, clinical studies have shown that patients with primary aldosteronism exhibit impaired glucose tolerance. 4 Some possible mechanisms of insulin resistance induced by aldosterone have been considered, such as a low serum potassium concentration, and direct effects of aldosterone on insulin signaling. 5,6 Previously, we have demonstrated that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs) via the downregulation of insulin receptor substrate-1, a key molecule of insulin signaling pathway. 7 Our data also clearly showed that aldosterone attenuates glucose metabolism in VSMCs. However, the precise molecular mechanisms responsible for aldosterone-induced VSMC insulin resistance and proatherogenic changes have not been identified. Conclusion-AldosteroneInsulin induces various actions, such as glucose metabolism and normal cell physiology, by binding to the insulin receptor (IR). 8 The VSMCs express not only IR but also insulin-like growth factor-1 receptor (IGF1R). 8 Compared with IR, IGF1R is more ab...

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“…Hybrid receptors have been reported to function as IGF-IR thus having a high affinity for IGF-I but not for insulin (Soos et al, 1993). The fact that the IR β-subunit immunoprecipitated with antibodies against the IGF-IR was not activated by insulin ( Figure 1) and that the IR was activated by IGF-I 10 -8 M in preadipocytes but not in adipocytes is probably explained by insulin/IGF-I hybrid receptors (Frattali,Pessin, 1993;Engberding et al, 2009). …”

Section: Discussionmentioning

confidence: 98%

Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes – Role of insulin and IGF-I receptors

Bäck

Brännmark

Strålfors

et al. 2011

Molecular and Cellular Endocrinology

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Insulin-Like Growth Factor-1 Receptor Expression Masks the Antiinflammatory and Glucose Uptake Capacity of Insulin in Vascular Smooth Muscle Cells

Cited by 42 publications

References 54 publications

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor

Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes – Role of insulin and IGF-I receptors

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