Expression of IGF-I, IGF-I receptor and IGF binding proteins -1, -2, -3, -4 and -5 in human atherectomy specimens

Grant, M.B.; Wargovich, Thomas J.; Ellis, E. Ann; Tarnuzzer, Roy; Caballero, Sergio; Estes, Kerry S.; Rossing, Maria; Spoerri, P.E.; Pepine, Carl J.

doi:10.1016/s0167-0115(96)00124-3

Cited by 52 publications

(43 citation statements)

References 30 publications

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“…IGF-1, AspB10 and glargine produced a prominent activation of Akt and were significantly more potent than regular insulin. This is consistent with the well established role of Akt in the regulation of DNA synthesis, cell proliferation and cell survival [25][26][27]. Knockdown of IGF-1R by >95% resulted in a substantially decreased Akt phosphorylation upon treatment with IGF-1, and glargine remained at a high level, while the insulinstimulated phosphorylation was significantly reduced by 40%.…”

Section: Discussionsupporting

confidence: 88%

“…Proliferation and migration of smooth muscle cells in response to growth factors represents a key step in the initiation of atherosclerosis [24] and it has been shown that IGF-1 may exert a prominent stimulatory action on this process [25,26]. Some insulin analogues were reported to exhibit a markedly increased IGF-1R affinity and mitogenic potency, which may represent a still undefined safety risk [20] regarding atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

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IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

et al. 2007

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Aims/hypothesis Mitogenic activity of insulin and insulin analogues and the involvement of the IGF-1 receptor (IGF-1R) is still a controversial issue. We compared levels of the proteins IGF-1R and insulin receptor (InsR) in fibroblasts and smooth muscle cells from healthy donors and assessed the downstream signalling and growth-promoting activity of insulin and insulin analogues. Methods DNA synthesis was monitored in human fibroblasts and coronary artery smooth muscle cells. Using small interfering RNAs, the levels of IGF-1 and InsR were reduced by 95 and 75%, respectively. Results Enhanced mitogenic potency of insulin and insulin analogues was observed which correlated with increased levels of IGF-1R and/or IRS-1. A reduction in the IGF-1R level significantly blunted stimulation of Akt phosphorylation by IGF-1, AspB10 and glargine by 72, 58 and 40%, respectively. Akt phosphorylation in response to insulin remained unaffected. Silencing of InsR did not significantly alter Akt phosphorylation in response to IGF-1, AspB10 and glargine. IGF-1R knockdown reduced the stimulation of DNA synthesis in response to IGF-1 and glargine to a level identical to that produced by insulin. Conclusions/interpretation These data show a prominent role of IGF-1R/Akt signalling in mediating the mitogenic effects of insulin analogues. Regular insulin stimulates DNA synthesis by exclusively activating InsR, whereas insulin analogues mainly signal through IGF-1R. It is suggested that inter-individual differences in the levels of proteins of the IGF-1R system may function as a critical determinant of the mitogenic potency of insulin analogues.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

et al. 2007

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“…Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4)(5)(6)(7)(8)(9)(10)(11)(12)(13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).…”

mentioning

confidence: 99%

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

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We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

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“…Increasing age and male gender are key risk factors for AAA (7). IGF1, IGF1 receptors and IGFBPs are expressed in vascular smooth muscle cells (VSMC) of human atherosclerotic plaques (8), and lower circulating levels of IGF1 have been associated with the incidence of cardiovascular events and stroke in previous studies (9,10). IGF1 concentration was reported to be decreased in human AAA tissue while concentrations of IGFBP1 and IGFBP3 were increased, raising the possibility that the IGF1 system contributes to the pathophysiology of AAA (11).…”

Section: Introductionmentioning

confidence: 99%

Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men

Yeap

Chubb

McCaul

et al. 2012

European Journal of Endocrinology

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Objective: Abdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men. Design: A cross-sectional analysis involving 3981 community-dwelling men aged 70-89 years was performed. Methods: Abdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays. Results: After adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 S.D. increase 1.18, 95% confidence interval (CI) 1.05-1.33, PZ0.006), as was the ratio of IGF1/IGFBP3 (ORZ1.22, 95% CI 1.10-1.35, P!0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: ORZ1.80, 95% CI 1.20-2.70, PZ0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: ORZ2.52, 95% CI 1.59-4.02, P!0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (bZ0.200, 95% CI 0.043-0.357, PZ0.012 and bZ0.274, 95% CI 0.098-0.449, PZ0.002 respectively). Conclusions: In older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.

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Expression of IGF-I, IGF-I receptor and IGF binding proteins -1, -2, -3, -4 and -5 in human atherectomy specimens

Cited by 52 publications

References 30 publications

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men

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