Abstract
Purpose
To investigate the relationship between angiopoietin-like protein 4 (ANGPTL-4) and vascular endothelial growth factor (VEGF) in the serum and vitreous of eyes in patients with proliferative diabetic retinopathy (PDR).
Methods
Thirty-five eyes of 35 patients with PDR, 20 eyes of 20 patients with non-proliferative diabetic retinopathy, 20 eyes of 20 patients with diabetes but no diabetic retinopathy, and 14 eyes of 14 nondiabetic patients with an idiopathic macular hole (IMH) were recruited from Shanghai First People’s Hospital. The ANGPTL-4 and VEGF concentrations were determined using enzyme-linked immunosorbent assays. Group means were compared using one-way analysis of variance with GraphPad Prism 4.0 and SPSS ver. 17.0. The research followed the tenets of the Declaration of Helsinki.
Results
The ANGPTL-4 and VEGF levels were significantly higher in the vitreous and serum of patients with PDR compared with patients with IMH. There were significant correlations between the ANGPTL-4 and VEGF levels in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated in patients with PDR. The ANGPTL-4 in both the vitreous and serum correlated with the serum triglyceride and high-density lipoprotein cholesterol levels.
Conclusions
The ANGPTL-4 levels were markedly elevated and the ANGPTL-4 expression was directly correlated with the VEGF expression in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated with serum lipids in patients with PDR. Our results suggest that the ANGPTL-4 may be used as a new therapeutic target for the treatment of PDR.
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References
Zheng B, Li T, Chen H, Xu X, Zheng Z (2011) Correlation between ficolin-3 and vascular endothelial growth factor-to-pigment epithelium-derived factor ratio in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 152:1039–1043. doi:10.1016/j.ajo.2011.05.022
Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R (1998) Diabetic retinopathy. Diabetes Care 21:143–156
Yokouchi H, Eto K, Nishimura W, Takeda N, Kaburagi Y, Yamamoto S, Yasuda K (2013) Angiopoietin-like protein 4 (ANGPTL4) is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells. Acta Ophthalmol (Copenh) 91:e289–e297. doi:10.1111/aos.12097
Schwartzman ML, Iserovich P, Gotlinger K, Bellner L, Dunn MW, Sartore M, Grazia Pertile M, Leonardi A, Sathe S, Beaton A, Trieu L, Sack R (2010) Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes 59:1780–1788. doi:10.2337/db10-0110
Georgiadi A, Wang Y, Stienstra R, Tjeerdema N, Janssen A, Stalenhoef A, van der Vliet JA, de Roos A, Tamsma JT, Smit JW, Tan NS, Muller M, Rensen PC, Kersten S (2013) Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development. Arterioscler Thromb Vasc Biol 33:1529–1537. doi:10.1161/ATVBAHA.113.301698
Makoveichuk E, Vorrsjo E, Olivecrona T, Olivecrona G (2013) Inactivation of lipoprotein lipase in 3T3-L1 adipocytes by angiopoietin-like protein 4 requires that both proteins have reached the cell surface. Biochem Biophys Res Commun 441:941–946. doi:10.1016/j.bbrc.2013.11.013
Santulli G (2014) Angiopoietin-like proteins: a comprehensive look. Front Endocrinol (Lausanne) 5:4. doi:10.3389/fendo.2014.00004
Tjeerdema N, Georgiadi A, Jonker JT, van Glabbeek M, Alizadeh Dehnavi R, Tamsma JT, Smit JW, Kersten S, Rensen PC (2014) Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes. BMJ Open Diabetes Res Care 2, e000034. doi:10.1136/bmjdrc-2014-000034
Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, Liou GI, Caldwell RW (2005) Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr Drug Targets 6:511–524
Xu X, Zhu Q, Xia X, Zhang S, Gu Q, Luo D (2004) Blood-retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats. Curr Eye Res 28:251–256
Zheng Z, Chen H, Ke G, Fan Y, Zou H, Sun X, Gu Q, Xu X, Ho PC (2009) Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway. Diabetes 58:954–964. doi:10.2337/db07-1524
Lu QY, Chen W, Lu L, Zheng Z, Xu X (2014) Involvement of RhoA/ROCK1 signaling pathway in hyperglycemia-induced microvascular endothelial dysfunction in diabetic retinopathy. Int J Clin Exp Pathol 7:7268–7277
Lu Q, Lu L, Chen W, Chen H, Xu X, Zheng Z (2015) RhoA/mDia-1/profilin-1 signaling targets microvascular endothelial dysfunction in diabetic retinopathy. Graefe’s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle. Ophthalmologie 253:669–680. doi:10.1007/s00417-015-2985-3
Nakao S, Arima M, Ishikawa K, Kohno R, Kawahara S, Miyazaki M, Yoshida S, Enaida H, Hafezi-Moghadam A, Kono T, Ishibashi T (2012) Intravitreal anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in retinal angiogenesis. Invest Ophthalmol Vis Sci 53:4323–4328. doi:10.1167/iovs.11-9119
Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P, Germain S (2003) Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 162:1521–1528. doi:10.1016/S0002-9440(10)64285-X
Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D, Kersten S, Witte DP, Hirsch R, Thornton S (2005) Angiopoietin-like-4 is a potential angiogenic mediator in arthritis. Clin Immunol 115:93–101. doi:10.1016/j.clim.2004.12.002
Perdiguero EG, Galaup A, Durand M, Teillon J, Philippe J, Valenzuela DM, Murphy AJ, Yancopoulos GD, Thurston G, Germain S (2011) Alteration of developmental and pathological retinal angiogenesis in angptl4-deficient mice. J Biol Chem 286:36841–36851. doi:10.1074/jbc.M111.220061
Ito Y, Oike Y, Yasunaga K, Hamada K, Miyata K, Matsumoto S, Sugano S, Tanihara H, Masuho Y, Suda T (2003) Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4. Cancer Res 63:6651–6657
Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK, LaNoue KF, Norbury CC, Quinn PG, Sandirasegarane L, Simpson IA (2006) Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55:2401–2411. doi:10.2337/db05-1635
Jialal I, Rajamani U, Siegel D (2014) The role of dyslipidemia in diabetic retinopathy: a brighter focus? J Diabetes Complicat 28:753–754. doi:10.1016/j.jdiacomp.2014.07.002
Sun CY, Lee CC, Hsieh MF, Chen CH, Chou KM (2014) Clinical association of circulating VEGF-B levels with hyperlipidemia and target organ damage in type 2 diabetic patients. J Biol Regul Homeost Agents 28:225–236
Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Muller M, Kersten S (2006) The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem 281:934–944. doi:10.1074/jbc.M506519200
Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P (2005) Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 146:4943–4950. doi:10.1210/en.2005-0476
Acknowledgments
This work was supported by grants from the National Nature Science Foundation of China (81271032). The sponsor had no role in the design or conduct of this research.
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All authors certify that we have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. Informed consent was obtained from all individual participants included in the study.
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Qianyi Lu and Wenjun Zou contributed equally to this work.
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Supplementary Table 1
One-sample Kolmogorov–Smirnov test. (DOC 36 kb)
Supplementary Table 2
Pearson’s correlation tests with r and p values between ANGPTL-4 and other factors in PDR patients. (DOC 31 kb)
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Lu, Q., Zou, W., Chen, B. et al. ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 254, 1281–1288 (2016). https://doi.org/10.1007/s00417-015-3187-8
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DOI: https://doi.org/10.1007/s00417-015-3187-8