Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor

Zhang, Qiuhua; Soderland, Carl; Steinle, Jena J.

doi:10.1007/s10495-012-0793-3

Cited by 17 publications

(21 citation statements)

References 36 publications

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“…By using a mutant form of IGFBP-3 that cannot bind IGF-1, it is possible to observe IGF-1 independent actions of IGFBP-3. Under these conditions (in our case, transfection of REC with mutant non-binding, IGFBP-3 NB plasmid), we found that overexpression of IGFBP-3 NB led to a reduction in TNF-α levels and a subsequent reduction in REC apoptosis (Zhang et al, 2013a,b). The studies described here also use IGFBP-3 NB plasmid and thus, all the findings contained in this report are limited to actions of IGFBP-3 that are independent of IGF-1 binding.…”

Section: Introductionmentioning

confidence: 67%

“…Previous studies have demonstrated that this model system demonstrates many features of retinal endothelial cells in vivo from diabetic animals (Zhang et al, 2012, 2013a,b). These common features, including high levels of TNF-α as well as vascular cell death, are causative in the development of diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 86%

“…Various mediators, such as tumor necrosis factor alpha (TNF-α), the insulin-like growth factor 1(IGF-1)/insulin like growth factor binding protein (IGFBP) system and vascular endothelial growth factor (VEGF) are known to regulate cell apoptotic pathways in various cell types including REC (Ben-Mahmud et al, 2004; Kielczewski et al, 2011; Titchenell and Antonetti, 2013); however, the specific pathways involved are unclear. We have previously reported that IGFBP-3 inhibits TNF-α production, leading to an inhibition of REC apoptosis (Zhang et al, 2013a,b). Building on this important finding, our goal in the current study is to uncover the mechanistic pathways that underlie IGFBP-3 regulation of TNF-α and REC apoptosis, and specifically to determine if binding of IGFBP-3 to its receptor, LRP1, is involved in its protective effects.…”

Section: Introductionmentioning

confidence: 98%

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IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against Retinal Endothelial Cell Apoptosis

Zhang

Steinle

2014

Microvascular Research

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In models of diabetic retinopathy, insulin-like growth factor binding protein-3 (IGFBP-3) protects against tumor necrosis factors-alpha (TNF-α)-mediated apoptosis of retinal microvascular endothelial cells (REC), but the underlying mechanisms are unclear. Our current findings suggest that at least two discrete but complimentary pathways contribute to the protective effects of IGFBP-3; 1) IGFBP-3 directly activates the c-Jun kinase/tissue inhibitor of metalloproteinase-3/TNF-α converting enzyme (c-Jun/TIMP-3/TACE), pathway, which in turn inhibits TNF-α production; 2) IGFBP-3 acts through the IGFBP-3 receptor, low-density lipoprotein receptor-related protein 1 (LRP1), to inhibit signaling of TNF-α receptor 2 (TNFR2). Combined, these two IGFBP-3 pathways substantially reduce REC apoptosis and offer potential targets for the treatment of diabetic retinopathy.

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 98%

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IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against Retinal Endothelial Cell Apoptosis

Zhang

Steinle

2014

Microvascular Research

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“…A subsequent study showed that IGFBP3 increased tube formation and angiogenesis-related gene expression including VEGF, MT1-MMP and MMP2, as well as increasing MMP2, and MMP9 activation (Granata et al 2007). Incubation in high glucose increased death of primary human retinal microvascular endothelial cells and IGFBP3 inhibited this effect via the LRP1/TGFB receptor (Zhang et al 2013a), which has been reported to mediate IGF-independent actions of this IGFBP (Huang et al 2003). The anti-apoptotic effect of IGFBP3 was associated with increased AKT phosphorylation and Bcl-xL levels while cytochrome c, BAX and cleaved caspase 3 were decreased in these cells.…”

Section: Insulin-like Growth Factor-binding Proteinsmentioning

confidence: 96%

Endothelial cells and the IGF system

Bach¹

2014

Journal of Molecular Endocrinology

153

118

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Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.

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“…Increased levels of IGFBP-3 in the knockdown mice can significantly reduce TNFα levels through activation of the Jun pathway (Zhang et al, in revision). Additionally, Compound 49b-induced increases in IGFBP-3 levels after ocular blast likely reduced pro-apoptotic factors, Bax, cytochrome C, and cleaved caspase 3, through activation of its receptor [12]. Thus, we conclude that Compound 49b is effective in protecting the retina against blast-induced injury through increasing IGFBP-3 levels, as well as reducing TNFα signaling.…”

Section: 0 Discussionmentioning

confidence: 90%

Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in retina

et al. 2014

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Ocular trauma affects 20% of Americans in their lifetime and can cause permanent visual system damage. We have used a mouse model of ocular trauma (exposure to an air blast from a paintball gun) to examine pathways that trigger the resulting retinal damage and to develop treatment strategies that might ameliorate the deleterious effects of trauma on retinal tissue. Our previous studies have shown that ocular blast causes an increase in protein levels of inflammatory mediators and apoptotic factors, including tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL-1β), as well as the apoptotic markers, Bax, cytochrome C, and cleaved caspase 3. Furthermore, topical treatment by eye drop application of a β-adrenergic receptor agonist, Compound 49b, was shown to decrease these inflammation/apoptosis markers and thus ameliorate the effects of blast trauma. We postulate that the protective effect of Compound 49b may be linked to its demonstrated ability to activate the β-adrenergic receptor and in turn trigger production of insulin-like growth factor binding protein 3 (IGFBP-3). In the current study, we tested this hypothesis using mice with minimal IGFBP-3 activity (IGFBP-3 knockdown mouse) vs. wildtype mice. We found that ocular blast alone did not affect IGFBP-3 levels in retinas of wild type or knockdown mice and surprisingly, the lower levels of IGFBP-3 in knockdown animals did not exacerbate the blast-induced increase in protein levels of inflammation/apoptosis markers. Nevertheless, the levels of IGFBP-3 were significantly increased in knockdown mouse retina by treatment with Compound 49b 24 hours post-trauma and as expected, the increase in IGFBP-3 was linked to a decrease in inflammation/apoptosis markers. We conclude that while lowered IGFBP-3 may not make the retina more vulnerable to blast injury, an increase in IGFBP-3 post-trauma may play an important role in limiting trauma-induced inflammatory and apoptotic pathways leading to retinal damage. Eye drop application of the β-adrenergic receptor agonist, Compound 49b, provides a promising treatment strategy for increasing IGFBP-3 levels to promote recovery from retinal inflammation and apoptosis after ocular blast.

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Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor

Cited by 17 publications

References 36 publications

IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against Retinal Endothelial Cell Apoptosis

IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against Retinal Endothelial Cell Apoptosis

Endothelial cells and the IGF system

Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in retina

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