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Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 2/2018

Open Access 01-02-2018 | Basic Science

Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration

Authors: Zygoula Ioanna, Schori Christian, Grimm Christian, Barthelmes Daniel

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 2/2018

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Abstract

Purpose

Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins.

Methods

Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA).

Results

The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients.

Conclusions

nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases.
Literature
1.
go back to reference Klein R, Klein BE, Linton KL (1992) Prevalence of age-related maculopathy. Beaver Dam Eye Study Ophthalmol 99:933–943 Klein R, Klein BE, Linton KL (1992) Prevalence of age-related maculopathy. Beaver Dam Eye Study Ophthalmol 99:933–943
2.
go back to reference Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related maculopathy in Australia. Blue Mountains Eye Study Ophthalmol 102:1450–1460 Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related maculopathy in Australia. Blue Mountains Eye Study Ophthalmol 102:1450–1460
3.
go back to reference Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT (1995) The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 102:205–210CrossRefPubMed Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT (1995) The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 102:205–210CrossRefPubMed
4.
go back to reference Group MPS (1990) Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Results of a randomized clinical trial. Macular photocoagulation study group. Arch Ophthalmol 108:816–824CrossRef Group MPS (1990) Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Results of a randomized clinical trial. Macular photocoagulation study group. Arch Ophthalmol 108:816–824CrossRef
5.
go back to reference (1993) Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 111: 1200-1209 (1993) Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 111: 1200-1209
8.
go back to reference Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N (2006) Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology 113(633):e631–e634. https://doi.org/10.1016/j.ophtha.2005.10.052 Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N (2006) Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology 113(633):e631–e634. https://​doi.​org/​10.​1016/​j.​ophtha.​2005.​10.​052
12.
14.
go back to reference DaCosta J (2013) Minocycline protects retinal pigment epithelial cells from hypoxia. ARVO Meeting Abstr 54:4108 DaCosta J (2013) Minocycline protects retinal pigment epithelial cells from hypoxia. ARVO Meeting Abstr 54:4108
16.
go back to reference Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514CrossRefPubMedPubMedCentral Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514CrossRefPubMedPubMedCentral
17.
go back to reference Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A 90:4304–4308CrossRefPubMedPubMedCentral Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A 90:4304–4308CrossRefPubMedPubMedCentral
18.
go back to reference Vadlapatla RK, Vadlapudi AD, Pal D, Mukherji M, Mitra A (2013) Ritonavir inhibits HIF-1{alpha} mediated VEGF expression in retinal pigment epithelial cells. ARVO Meeting Abstr 54:3275 Vadlapatla RK, Vadlapudi AD, Pal D, Mukherji M, Mitra A (2013) Ritonavir inhibits HIF-1{alpha} mediated VEGF expression in retinal pigment epithelial cells. ARVO Meeting Abstr 54:3275
19.
go back to reference Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA (1999) Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci 40:182–189PubMed Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA (1999) Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci 40:182–189PubMed
20.
go back to reference Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81:154–162CrossRefPubMedPubMedCentral Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81:154–162CrossRefPubMedPubMedCentral
21.
go back to reference Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37:855–868PubMed Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37:855–868PubMed
23.
go back to reference Wang F, Rendahl KG, Manning WC, Quiroz D, Coyne M, Miller SS (2003) AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat. Invest Ophthalmol Vis Sci 44:781–790CrossRefPubMed Wang F, Rendahl KG, Manning WC, Quiroz D, Coyne M, Miller SS (2003) AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat. Invest Ophthalmol Vis Sci 44:781–790CrossRefPubMed
24.
go back to reference Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty GA, Semenza GL, Montaner S, Sodhi A (2015) Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci U S A 112:E3030–E3039. https://doi.org/10.1073/pnas.1423765112 CrossRefPubMedPubMedCentral Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty GA, Semenza GL, Montaner S, Sodhi A (2015) Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci U S A 112:E3030–E3039. https://​doi.​org/​10.​1073/​pnas.​1423765112 CrossRefPubMedPubMedCentral
25.
go back to reference Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart JM, Noel A, Munaut C (2003) Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3186–3193CrossRefPubMed Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart JM, Noel A, Munaut C (2003) Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3186–3193CrossRefPubMed
29.
go back to reference Mirshahi A, Hoehn R, Lorenz K, Kramann C, Baatz H (2012) Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J Ophthalmic Vis Res 7:39–44PubMedPubMedCentral Mirshahi A, Hoehn R, Lorenz K, Kramann C, Baatz H (2012) Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J Ophthalmic Vis Res 7:39–44PubMedPubMedCentral
31.
go back to reference Stitt AW, Gardiner TA, Archer DB (1995) Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br J Ophthalmol 79:362–367CrossRefPubMedPubMedCentral Stitt AW, Gardiner TA, Archer DB (1995) Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br J Ophthalmol 79:362–367CrossRefPubMedPubMedCentral
32.
go back to reference Boeri D, Maiello M, Lorenzi M (2001) Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 50:1432–1439CrossRefPubMed Boeri D, Maiello M, Lorenzi M (2001) Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 50:1432–1439CrossRefPubMed
34.
go back to reference Jiang F, Tang YT, Guo L, Jiao XY (2013) The role of insulin-like growth factor I and hypoxia inducible factor 1alpha in vascular endothelial growth factor expression in type 2 diabetes. Ann Clin Lab Sci 43:37–44PubMed Jiang F, Tang YT, Guo L, Jiao XY (2013) The role of insulin-like growth factor I and hypoxia inducible factor 1alpha in vascular endothelial growth factor expression in type 2 diabetes. Ann Clin Lab Sci 43:37–44PubMed
39.
go back to reference Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248CrossRefPubMed Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248CrossRefPubMed
40.
go back to reference Larsson A, Skoldenberg E, Ericson H (2002) Serum and plasma levels of FGF-2 and VEGF in healthy blood donors. Angiogenesis 5:107–110CrossRefPubMed Larsson A, Skoldenberg E, Ericson H (2002) Serum and plasma levels of FGF-2 and VEGF in healthy blood donors. Angiogenesis 5:107–110CrossRefPubMed
41.
go back to reference Wognum AW, Lam V, Goudsmit R, Krystal G (1990) A specific in vitro bioassay for measuring erythropoietin levels in human serum and plasma. Blood 76:1323–1329PubMed Wognum AW, Lam V, Goudsmit R, Krystal G (1990) A specific in vitro bioassay for measuring erythropoietin levels in human serum and plasma. Blood 76:1323–1329PubMed
42.
go back to reference Bruno CM, Neri S, Sciacca C, Bertino G, Di Prima P, Cilio D, Pellicano R, Caruso L, Cristaldi R (2004) Plasma erythropoietin levels in anaemic and non-anaemic patients with chronic liver diseases. World J Gastroenterol 10:1353–1356CrossRefPubMedPubMedCentral Bruno CM, Neri S, Sciacca C, Bertino G, Di Prima P, Cilio D, Pellicano R, Caruso L, Cristaldi R (2004) Plasma erythropoietin levels in anaemic and non-anaemic patients with chronic liver diseases. World J Gastroenterol 10:1353–1356CrossRefPubMedPubMedCentral
43.
go back to reference Jonker JT, Smit JW, Hammer S, Snel M, van der Meer RW, Lamb HJ, Mattijssen F, Mudde K, Jazet IM, Dekkers OM, de Roos A, Romijn JA, Kersten S, Rensen PC (2013) Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes. Am J Clin Nutr 97:255–260. https://doi.org/10.3945/ajcn.112.043687 CrossRefPubMed Jonker JT, Smit JW, Hammer S, Snel M, van der Meer RW, Lamb HJ, Mattijssen F, Mudde K, Jazet IM, Dekkers OM, de Roos A, Romijn JA, Kersten S, Rensen PC (2013) Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes. Am J Clin Nutr 97:255–260. https://​doi.​org/​10.​3945/​ajcn.​112.​043687 CrossRefPubMed
46.
go back to reference Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, Gedrich K, Pollmacher T (2006) TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population. Eur Cytokine Netw 17:196–201PubMed Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, Gedrich K, Pollmacher T (2006) TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population. Eur Cytokine Netw 17:196–201PubMed
49.
go back to reference Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22:1–29CrossRefPubMed Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22:1–29CrossRefPubMed
50.
go back to reference Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, Suzuma I, Ohashi H, Ojima T, Murakami T, Kobayashi T, Masuda S, Nagao M, Yoshimura N, Takagi H (2005) Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353:782–792. https://doi.org/10.1056/NEJMoa041773 CrossRefPubMed Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, Suzuma I, Ohashi H, Ojima T, Murakami T, Kobayashi T, Masuda S, Nagao M, Yoshimura N, Takagi H (2005) Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353:782–792. https://​doi.​org/​10.​1056/​NEJMoa041773 CrossRefPubMed
54.
go back to reference Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J (2001) Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 489:270–276CrossRefPubMed Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J (2001) Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 489:270–276CrossRefPubMed
55.
go back to reference Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M (2002) Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol 134:348–353CrossRefPubMed Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M (2002) Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol 134:348–353CrossRefPubMed
61.
go back to reference Lip PL, Belgore F, Blann AD, Hope-Ross MW, Gibson JM, Lip GY (2000) Plasma VEGF and soluble VEGF receptor FLT-1 in proliferative retinopathy: relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci 41:2115–2119PubMed Lip PL, Belgore F, Blann AD, Hope-Ross MW, Gibson JM, Lip GY (2000) Plasma VEGF and soluble VEGF receptor FLT-1 in proliferative retinopathy: relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci 41:2115–2119PubMed
64.
go back to reference Kakizawa H, Itoh M, Itoh Y, Imamura S, Ishiwata Y, Matsumoto T, Yamamoto K, Kato T, Ono Y, Nagata M, Hayakawa N, Suzuki A, Goto Y, Oda N (2004) The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism 53:550–555CrossRefPubMed Kakizawa H, Itoh M, Itoh Y, Imamura S, Ishiwata Y, Matsumoto T, Yamamoto K, Kato T, Ono Y, Nagata M, Hayakawa N, Suzuki A, Goto Y, Oda N (2004) The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism 53:550–555CrossRefPubMed
67.
go back to reference Ogata N, Matsuoka M, Matsuyama K, Shima C, Tajika A, Nishiyama T, Wada M, Jo N, Higuchi A, Minamino K, Matsunaga H, Takeda T, Matsumura M (2007) Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab 92:1176–1179. https://doi.org/10.1210/jc.2006-2249 CrossRefPubMed Ogata N, Matsuoka M, Matsuyama K, Shima C, Tajika A, Nishiyama T, Wada M, Jo N, Higuchi A, Minamino K, Matsunaga H, Takeda T, Matsumura M (2007) Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab 92:1176–1179. https://​doi.​org/​10.​1210/​jc.​2006-2249 CrossRefPubMed
70.
go back to reference Machalinska A, Safranow K, Mozolewska-Piotrowska K, Dziedziejko V, Karczewicz D (2012) PEDF and VEGF plasma level alterations in patients with dry form of age-related degeneration--a possible link to the development of the disease. Klin Ocz 114:115–120 Machalinska A, Safranow K, Mozolewska-Piotrowska K, Dziedziejko V, Karczewicz D (2012) PEDF and VEGF plasma level alterations in patients with dry form of age-related degeneration--a possible link to the development of the disease. Klin Ocz 114:115–120
71.
go back to reference Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544CrossRefPubMed Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544CrossRefPubMed
73.
go back to reference Xin X, Rodrigues M, Umapathi M, Kashiwabuchi F, Ma T, Babapoor-Farrokhran S, Wang S, Hu J, Bhutto I, Welsbie DS, Duh EJ, Handa JT, Eberhart CG, Lutty G, Semenza GL, Montaner S, Sodhi A (2013) Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. Proc Natl Acad Sci U S A 110:E3425–E3434. https://doi.org/10.1073/pnas.1217091110 CrossRefPubMedPubMedCentral Xin X, Rodrigues M, Umapathi M, Kashiwabuchi F, Ma T, Babapoor-Farrokhran S, Wang S, Hu J, Bhutto I, Welsbie DS, Duh EJ, Handa JT, Eberhart CG, Lutty G, Semenza GL, Montaner S, Sodhi A (2013) Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. Proc Natl Acad Sci U S A 110:E3425–E3434. https://​doi.​org/​10.​1073/​pnas.​1217091110 CrossRefPubMedPubMedCentral
Metadata
Title
Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration
Authors
Zygoula Ioanna
Schori Christian
Grimm Christian
Barthelmes Daniel
Publication date
01-02-2018
Publisher
Springer Berlin Heidelberg
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 2/2018
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-017-3846-z

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