Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy

Michal Laniado Schwartzman, Pavel Iserovich, Katherine Gotlinger, Lars Bellner, Michael W Dunn, Mauro Sartore, Maria Grazia Pertile, Andrea Leonardi, Sonal Sathe, Ann Beaton, Lynn Trieu, Robert Sack, Michal Laniado Schwartzman, Pavel Iserovich, Katherine Gotlinger, Lars Bellner, Michael W Dunn, Mauro Sartore, Maria Grazia Pertile, Andrea Leonardi, Sonal Sathe, Ann Beaton, Lynn Trieu, Robert Sack

Abstract

Objective: This study was aimed at obtaining a profile of lipids and proteins with a paracrine function in normal and diabetic vitreous and exploring whether the profile correlates with retinal pathology.

Research design and methods: Vitreous was recovered from 47 individuals undergoing vitreoretinal surgery: 16 had nonproliferative diabetic retinopathy (NPDR), 15 had proliferative diabetic retinopathy, 7 had retinal detachments, and 9 had epiretinal membranes. Protein and lipid autacoid profiles were determined by protein arrays and mass spectrometry-based lipidomics.

Results: Vitreous lipids included lipoxygenase (LO)- and cytochrome P450 epoxygenase (CYP)-derived eicosanoids. The most prominent LO-derived eicosanoid was 5-hydroxyeicosate traenoic acid (HETE), which demonstrated a diabetes-specific increase (P = 0.027) with the highest increase in NPDR vitreous. Vitreous also contained CYP-derived epoxyeicosatrienoic acids; their levels were higher in nondiabetic than diabetic vitreous (P < 0.05). Among inflammatory, angiogenic, and angiostatic cytokines and chemokines, only vascular endothelial growth factor (VEGF) showed a significant diabetes-specific profile (P < 0.05), although a similar trend was noted for tumor necrosis factor (TNF)-alpha. Soluble VEGF receptors R1 and R2 were detected in all samples with lowest VEGF-R2 levels (P < 0.05) and higher ratio of VEGF to its receptors in NPDR and PDR vitreous.

Conclusions: This study is the first to demonstrate diabetes-specific changes in vitreous lipid autacoids including arachidonate and docosahexanoate-derived metabolites indicating an increase in inflammatory versus anti-inflammatory lipid mediators that correlated with increased levels of inflammatory and angiogenic proteins, further supporting the notion that inflammation plays a role the pathogenesis of this disease.

Figures

FIG. 1.
FIG. 1.
Representative lipidomics of diabetic and nondiabetic vitreous. Each lipid is identified by its elution time and unique multiple reaction monitoring pair and quantified using standard curve of authentic standards. A: Elution profile of authentic standards. B: Lipid profile in a nondiabetic vitreous. C: Lipid profile of in a diabetic vitreous; x = unknown.
FIG. 2.
FIG. 2.
Levels of 5-HETE in nondiabetic and diabetic vitreous (A) and ERM, RD, NPDR, and PDR vitreous (B).
FIG. 3.
FIG. 3.
Levels of 14(15)-EET and 11(12)-EET in nondiabetic and diabetic vitreous and (A and C, respectively) and in ERM, RD, NPDR, and PDR vitreous (B and D, respectively).
FIG. 4.
FIG. 4.
Representative arrays of vitreous samples. Upper panel: Representative membranes of vitreous samples (300 μl) from individuals with an ERM and RD sample along with blank control. Lower panel: Representative membranes of pooled vitreal samples from individuals randomly selected with NPDR, ERM, and PDR (three samples of 700 μl each in each category) and a membrane probed with 700-μl samples of vitreous from an individual exhibiting a rapid disease progression (NPDR*). Array configuration and the sensitivity limits for each protein determined by the manufacturer are depicted in the table.
FIG. 5.
FIG. 5.
Ratios of VEGF to VEGFR1 and VEGFR2 in vitreous from patients with ERM, RD, NPDR, and PDR. Results are mean ± SE. *P < 0.05 vs. ERM.

References

    1. Kern TS: Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007;2007:95103.
    1. Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, Schraermeyer U, Kociok N, Fauser S, Kirchhof B, Kern TS, Adamis AP: A central role for inflammation in the pathogenesis of diabetic retinopathy. Faseb J 2004;18:1450–1452
    1. Banerjee S, Savant V, Scott RA, Curnow SJ, Wallace GR, Murray PI: Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders. Invest Ophthalmol Vis Sci 2007;48:2203–2207
    1. Murugeswari P, Shukla D, Rajendran A, Kim R, Namperumalsamy P, Muthukkaruppan V: Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and eales' disease. Retina 2008;28:817–824
    1. Spranger J, Osterhoff M, Reimann M, Möhlig M, Ristow M, Francis MK, Cristofalo V, Hammes HP, Smith G, Boulton M, Pfeiffer AF: Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes 2001;50:2641–2645
    1. Simó R, Carrasco E, García-Ramírez M, Hernández C: Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2006;2:71–98
    1. Hardy P, Beauchamp M, Sennlaub F, Jr, Gobeil F, Mwaikambo B, Lachapelle P, Chemtob S: Inflammatory lipid mediators in ischemic retinopathy. Pharmacol Rep 2005;57(Suppl.):169–190
    1. Gubitosi-Klug RA, Talahalli R, Du Y, Nadler JL, Kern TS: 5-Lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy. Diabetes 2008;57:1387–1393
    1. Laniado Schwartzman M, Green K, Edelhauser HF, Hackett RB, Hull DS, Potter DE, Tripathi RC: In Cytochrome P450 and Arachidonic Acid Metabolism in the Corneal Epithelium: Role in Inflammation New York, Plenum Press, 1997, p. 3–20
    1. Gronert K: Lipoxins in the eye and their role in wound healing. Prostaglandins Leukot Essent Fatty Acids 2005;73:221–229
    1. Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K, Zeldin DC, Liao JK: Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 1999;285:1276–1279
    1. Patil K, Bellner L, Cullaro G, Gotlinger KH, Dunn MW, Schwartzman ML: Heme oxygenase-1 induction attenuates corneal inflammation and accelerates wound healing after epithelial injury. Invest Ophthalmol Vis Sci 2008;49:3379–3386
    1. Sack RA, Conradi L, Krumholz D, Beaton A, Sathe S, Morris C: Membrane array characterization of 80 chemokines, cytokines, and growth factors in open- and closed-eye tears: angiogenin and other defense system constituents. Invest Ophthalmol Vis Sci 2005;46:1228–1238
    1. Li S, Sack R, Vijmasi T, Sathe S, Beaton A, Quigley D, Gallup M, McNamara NA: Antibody protein array analysis of the tear film cytokines. Optom Vis Sci 2008;85:653–660
    1. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG: Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 2004;101:8491–8496
    1. Capeans C, De Rojas MV, Lojo S, Salorio MS: C-C chemokines in the vitreous of patients with proliferative vitreoretinopathy and proliferative diabetic retinopathy. Retina 1998;18:546–550
    1. Maier R, Weger M, Haller-Schober EM, El-Shabrawi Y, Wedrich A, Theisl A, Aigner R, Barth A, Haas A: Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol Vis 2008;14:637–643
    1. Lewis RA, Austen KF, Soberman RJ: Leukotrienes and other products of the 5-lipoxygenase pathway: biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990;323:645–655
    1. Chen XS, Sheller JR, Johnson EN, Funk CD: Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 1994;372:179–182
    1. Funk CD, Chen XS: 5-Lipoxygenase and leukotrienes: transgenic mouse and nuclear targeting studies. Am J Respir Crit Care Med 2000;161:S120–S124
    1. Rubin P, Mollison KW: Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat 2007;83:188–197
    1. Talahalli R, Zarini S, Sheibani N, Murphy RC, Gubitosi-Klug RA: Increased synthesis of leukotrienes in the mouse model of diabetic retinopathy. Invest Ophthalmol Vis Sci 51:1699–1708
    1. Serhan CN, Chiang N, Van Dyke TE: Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008;8:349–361
    1. Augustin AJ, Grus FH, Koch F, Spitznas M: Detection of eicosanoids in epiretinal membranes of patients suffering from proliferative vitreoretinal diseases. Br J Ophthalmol 1997;81:58–60
    1. Hegde KR, Varma SD: Electron impact mass spectroscopic studies on mouse retinal fatty acids: effect of diabetes. Ophthalmic Res 2009;42:9–14
    1. Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem N, Jr, Serhan CN, Smith LE: Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 2007;13:868–873
    1. SanGiovanni JP, Chew EY: The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res 2005;24:87–138
    1. Spector AA: Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res 2009;50(Suppl.):S52–S56
    1. Spiecker M, Liao JK: Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids. Arch Biochem Biophys 2005;433:413–420
    1. Deng Y, Theken KN, Lee CR: Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation. J Mol Cell Cardiol 2010;48:331–341
    1. Moshal KS, Zeldin DC, Sithu SD, Sen U, Tyagi N, Kumar M, Hughes WM, Jr, Metreveli N, Rosenberger DS, Singh M, Vacek TP, Rodriguez WE, Ayotunde A, Tyagi SC: Cytochrome P450 (CYP) 2J2 gene transfection attenuates MMP-9 via inhibition of NF-kappabeta in hyperhomocysteinemia. J Cell Physiol 2008;215:771–781
    1. Zhang W, Otsuka T, Sugo N, Ardeshiri A, Alhadid YK, Iliff JJ, DeBarber AE, Koop DR, Alkayed NJ: Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia. Stroke 2008;39:2073–2078
    1. Sodhi K, Inoue K, Gotlinger K, Canestraro M, Vanella L, Kim DH, Manthati VL, Koduru SR, Falck JR, Schwartzman ML, Abraham NG: Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice. J Pharmacol Exp Ther 2009;331:906–916
    1. Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K, She H, Matsubara A, Miyahara S, Nakao S, Yin Y, Benowitz L, Hafezi-Moghadam A, Miller JW: Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci U S A 2007;104:2425–2430
    1. Cao Y, Chen C, Weatherbee JA, Tsang M, Folkman J: Gro-beta, a -C-X-C- chemokine, is an angiogenesis inhibitor that suppresses the growth of Lewis lung carcinoma in mice. J Exp Med 1995;182:2069–2077
    1. Matsunaga N, Chikaraishi Y, Izuta H, Ogata N, Shimazawa M, Matsumura M, Hara H: Role of soluble vascular endothelial growth factor receptor-1 in the vitreous in proliferative diabetic retinopathy. Ophthalmology 2008;115:1916–1922
    1. Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA: Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res 2006;82:798–806
    1. Adamiec-Mroczek J, Oficjalska-Młyńczak J: Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes: role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2008;246:1665–1670
    1. Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S: Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye 2006;20:1366–1369
    1. Limb GA, Hollifield RD, Webster L, Charteris DG, Chignell AH: Soluble TNF receptors in vitreoretinal proliferative disease. Invest Ophthalmol Vis Sci 2001;42:1586–1591

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