Insulin-like Growth Factor-I and its Receptor in Neovascular Age-Related Macular Degeneration

Lambooij, A. C.; Wely, Karel H. M. van; Lindenbergh-Kortleve, Dicky J.; Kuijpers, Robert W A M; Kliffen, Mike; Mooy, Cornelia M.

doi:10.1167/iovs.02-0410

Cited by 73 publications

(56 citation statements)

References 31 publications

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“…Furthermore, if this function is compromised, as is the case in patients harboring dSNPs, the balance shifts to favor angiogenesis and thereby permits the accumulation of the choroidal neovessels. This hypothesis predicts that suppression of IGF-1 has the potential to protect patients from developing NvAMD (64). These findings offer a complementary understanding of HtrA1's multiple functions, based on the catalogue of NvAMD-associated SNPs (2) and existing HtrA1 animal models (70,71).…”

Section: Discussionmentioning

confidence: 92%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular agerelated macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. Single nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1, 2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3). Furthermore, some of the disease-associated synonymous SNPs constitute the molecular underpinnings of pathology, meaning that they are enriched in affected human subjects and alter the gene product. For the majority (95%) of disease-associated synonymous SNPs, aberrant gene products were attributed to unstable mRNA transcripts with a reduced half-life or mutations in splice sites that resulted in exon skipping (4, 5). In other cases, synonymous SNPs caused translational defects independently of mRNA splicing errors (6-9).A parsimonious mechanism by which synonymous SNPs impact the integrity of protein products involves the alteration of codon usage. In vivo, folding of nascent proteins proceeds cotranslationally (10, 11) and is influenced by the rate of ribosome transit through the mRNA template. What distinguishes synonymous codons that encode a given degenerate amino acid is the abundance of their corresponding tRNA, which is lower for infrequently used codons than for frequently used codons (12, 13). Consequently, codon frequency can influence the rate of translation. Of note, codon bias has been widely described in prokaryotes and single-celled eukaryotes but less extensively in complex eukaryotes.In humans, correlations between optimum codon usage and either protein expression...

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Section: Discussionmentioning

confidence: 92%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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“…The IGF-1 produced in the transgenic retina accumulated in the aqueous humor and was thus available to IGF-1 receptors in the iris (8), probably leading to rubeosis iridis. VEGF production from the transgenic retina may also have contributed to this process.…”

Section: Figure 12mentioning

confidence: 99%

“…An increase of IGF-1 has been found in the vitreous of patients with diabetic retinopathy (5-7). IGF-1 receptors are widely distributed in the eye (8), and treatment of ischemia-induced mice with IGF-1 receptor antagonist prevents retinal neovascularization (9), which indicates a key role of IGF-1-mediated signaling. Furthermore, following hypoxia, vascular endothelial cell-specific IGF-1 receptor KO mice (VENIFARKO) show reduced retinal neovascularization (10).…”

Section: Introductionmentioning

confidence: 99%

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Ruberte

Ayuso²,

Navarro³

et al. 2004

J. Clin. Invest.

150

115

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IGF-1 has been associated with the pathogenesis of diabetic retinopathy, although its role is not fully understood. Here we show that normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 in the retina developed most alterations seen in human diabetic eye disease. A paracrine effect of IGF-1 in the retina initiated vascular alterations that progressed from nonproliferative to proliferative retinopathy and retinal detachment. Eyes from 2-month-old transgenic mice showed loss of pericytes and thickening of basement membrane of retinal capillaries. In mice 6 months and older, venule dilatation, intraretinal microvascular abnormalities, and neovascularization of the retina and vitreous cavity were observed. Neovascularization was consistent with increased IGF-1 induction of VEGF expression in retinal glial cells. In addition, IGF-1 accumulated in aqueous humor, which may have caused rubeosis iridis and subsequently adhesions between the cornea and iris that hampered aqueous humor drainage and led to neovascular glaucoma. Furthermore, all transgenic mice developed cataracts. These findings suggest a role of IGF-1 in the development of ocular complications in long-term diabetes. Thus, these transgenic mice may be used to study the mechanisms that lead to diabetes eye disease and constitute an appropriate model in which to assay new therapies.Nonstandard abbreviations used: glial fibrillar acidic protein (GFAP); intraocular pressure (IOP); intraretinal microvascular abnormalities (IRMAs); rat insulin promoter-I (RIP-I); streptozotocin (STZ); von Willebrand factor (vWF).

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“…It functions by blocking the local and systemic production of the growth hormone and insulin-like growth factor 1 (IGF-1), which are associated with endothelial cell proliferation [13,14,16,22,23] . Moreover, in addition to VEGF, IGF-1 has been implicated to promote angiogenesis in CNV [24][25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

Octreotide Inhibits Choroidal Neovascularization in Rats

Zhang²,

Xu³

et al. 2009

Ophthalmic Res

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Aims: Octreotide exhibits anti-angiogenic activity in animal models of retinopathy of prematurity and in clinical cases of proliferative diabetic retinopathy. In this study, we tested the applicability of using octreotide for inhibiting experimental choroidal neovascularization (CNV) in rats. Methods: Of 15 adult rats used, 3 served as non-laser-treated controls. CNV was induced in the right eye of the remaining 12 rats by laser photocoagulation. These 12 rats were divided into two groups (n = 6 each) which were retrobulbarly injected with octreotide (50 μg/kg) or phosphate-buffered saline (PBS) (0.15 ml) immediately and on day 3 after the first injection. Fluorescein angiography and quantitative analysis of the retinal pigment epithelium (RPE)-choroidal flat mounts were performed 14 days after the operation to evaluate the changes in the CNV lesions. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to compare the changes shown by the octreotide-, PBS-, and non-laser-treated rats (n = 3 each) with regard to mRNA levels of the vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-1 in the RPE-choroidal complex. Results: Octreotide treatment significantly inhibited fluorescein leakage and the extent of neovascularization as was observed in the flat mounts of choroidal tissue derived from the rats with induced CNV. The VEGF and IGF-1 mRNA levels were reduced following treatment with octreotide. Conclusion: The retrobulbar administration of octreotide may be an effective new therapeutic strategy for CNV.

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Insulin-like Growth Factor-I and its Receptor in Neovascular Age-Related Macular Degeneration

Cited by 73 publications

References 31 publications

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

Octreotide Inhibits Choroidal Neovascularization in Rats

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