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Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy

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Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy International Journal of Molecular Sciences Article Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy Albert L Lin 1, Richard J Roman 2 , Kathleen A Regan 3 , Charlotte A Bolch 4 , Ching-Jygh Chen 1 and Siva S. R. Iyer 4,* 1 Department of Ophthalmology, University of Mississippi School of Medicine, Jackson, MS 39216, USA; [email protected] (A.L.L.); [email protected] (C.-J.C.) 2 Department of Pharmacology and Toxicology, University of Mississippi School of Medicine, Jackson, MS 39216, USA; [email protected] 3 Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA; [email protected] 4 Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610, USA; [email protected] * Correspondence: ssr@ufl.edu; Tel.: +1-352-273-8777; Fax: +1-352-273-7402 Received: 30 August 2020; Accepted: 5 October 2020; Published: 9 October 2020 Abstract: Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative diabetic retinopathy versus controls. The results indicated that lipoxygenase and cytochrome P450-derived eicosanoids were elevated (5-HETE, 12-HETE, 20-HETE, and 20-COOH-AA), and there appeared to be no differences in levels measured in eyes with tractional retinal detachments versus those without. These results provide further insight into the pathogenesis of this disease and for the development of future potential therapeutic agents that target arachidonic acid metabolites to treat diabetic retinopathy. Keywords: vitreous; eicosanoids; proliferative diabetic retinopathy; tractional retinal detachment 1. Introduction Proliferative diabetic retinopathy (PDR) is a sight-threatening condition faced by many diabetic patients [1–5]. On the clinical spectrum of diabetic retinopathy, PDR is considered the advanced form of diabetic retinopathy, heralded by the formation of abnormal retinal neovascularization due to severe retinal ischemia. As a consequence of pathology at the vitreoretinal interface, these patients are at particular risk for permanent retinal damage without treatment [3,4]. Currently, there are multiple treatment options for PDR, of which the gold standard remains pan-retinal photocoagulation (PRP) [6]. In some cases, due to either poor visibility of the fundus or advanced disease, some patients cannot be adequately treated with PRP alone and must undergo pars plana vitrectomy [7]. During this surgery, the vitreous humor and its related posterior cortical attachments are removed, and pan-retinal photocoagulation is applied to the retina via an endolaser probe or indirect laser ophthalmoscopy. This surgery is commonly performed for non-clearing vitreous hemorrhages causing persistent vision loss. In very advanced disease, proliferative diabetic retinopathy can lead to tractional retinal detachments that often require extensive and complex surgical maneuvers for surgical success [8,9]. The visual prognosis for these patients can be quite poor despite successful surgical outcomes. Currently, vascular endothelial growth factor (VEGF) is the primary target of pharmacologic intervention for PDR. Prior research has confirmed elevations of VEGF in vitreous samples in diabetic Int. J. Mol. Sci. 2020, 21, 7451; doi:10.3390/ijms21207451 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 13 Currently, vascular endothelial growth factor (VEGF) is the primary target of pharmacologic intervention for PDR. Prior research has confirmed elevations of VEGF in vitreous samples in diabetic retinopathy [10], with VEGF increasing retinal endothelial permeability [11]. Targeting VEGF has beenInt. the J. Mol.paradigm Sci. 2020, 21for, 7451 treating diabetic retinopathy in current clinical therapy and is considered2 of 13 the standard of care for diabetic macular edema involving the central macula. More recent clinical researchretinopathy has demonstrated [10], with VEGF that increasing treating retinal proliferative endothelial diabetic permeability retinopathy [11]. Targeting patients VEGF with has intravitreal been ranibizumab,the paradigm an foranti treating-VEGF diabetic monoclonal retinopathy-antibody in current fragment, clinical therapyis not inferior and is considered to PRP [12] the standard. Other than steroidof care treatment, for diabetic drugs macular targeting edema non involving-VEGF thepathways central macula. of diabetic More retinopathy recent clinical have research yet to has enter clinicaldemonstrated practice. that treating proliferative diabetic retinopathy patients with intravitreal ranibizumab, anThe anti-VEGF current monoclonal-antibodyview concerning the fragment, pathogenesis is notinferior of PDR to involves PRP [12]. an Other intraocular than steroid impetus treatment, to form de-novodrugs aberrant targeting retinal non-VEGF vessels pathways to counteract of diabetic microvascular retinopathy have ischemia yet to [13,9] enter clinical. This impetus practice. consists of the actionThe of current the well view-established concerning thevascular pathogenesis endothelial of PDR involvesgrowth anfactor intraocular (VEGF), impetus and toother form pro- angiogenicde-novo aberrantand pro retinal-fibrotic vessels growth to counteract factors microvascular (e.g., connective ischemia [tissue9,13]. Thisgrowth impetus factor) consists [14 of–16]. the action of the well-established vascular endothelial growth factor (VEGF), and other pro-angiogenic Arachidonic acid (AA) derivatives (specifically, eicosanoids such as prostaglandins, prostacyclins, and pro-fibrotic growth factors (e.g., connective tissue growth factor) [14–16]. Arachidonic acid (AA) hydroxyeicosatetraenoic acid (HETEs), dihydroxyeicosatraenoic acid (DiHETEs), leukotrienes, and derivatives (specifically, eicosanoids such as prostaglandins, prostacyclins, hydroxyeicosatetraenoic epoxyeicosatracid (HETEs),ienoic dihydroxyeicosatraenoic acid (EETs) have garnered acid (DiHETEs), interest leukotrienes,, and have been and epoxyeicosatrienoic implicated in retina acidl pro- angiogenesis.(EETs) have A garnered summary interest, of the and three have pathways been implicated for the in retinalmetabolism pro-angiogenesis. of arachidonic A summary acid and of the productsthe three formed pathways is presented for the metabolism in Figure 1 of. Lipoxygenase arachidonic acid (LOX) and thepathways products catalyze formed isthe presented hydroxylation in of arachidonicFigure1. Lipoxygenase acid, and 5 (LOX)-HETE pathways, 12-HETE catalyze, and the15- hydroxylationHETE are the of primary arachidonic product acid, ands of 5-HETE,this activity (Figure12-HETE, 1) [17] and. Increased 15-HETE levels are the of primary12-LOX productshave been of thisobserved activity in (Figure a mouse1)[ model17]. Increased of diabetes levels [17] of and in the12-LOX retina have of a beenmouse observed model infor a retinopathy mouse model of of prematurity diabetes [17] (ROP) and in, thewhich retina is ofalso a mouse characterized model by neovascularizatiofor retinopathyn of of prematurity the retina. (ROP), Further, which pharmacologic is also characterized inhibition by neovascularization or 12-LOX deletion of the retina. lowered VEGFFurther, levels pharmacologicand decreased inhibition retinal neovascularization or 12-LOX deletion [17] lowered VEGF levels and decreased retinal neovascularization [17]. Figure 1. A schematic of arachidonic acid’s hydroxyeicosatetraenoic (HETE), and epoxyeicosatrienoic Figureacid 1. (EET) A schematic derivatives of arachidonic and their relationships. acid’s hydroxyeicosatetraenoic HETEs are created by both (HETE), the lipoxygenase and epoxyeicosatrienoic (5-HETE, acid12-HETE, (EET) derivat 15-HETE)ives and and their cytochrome relationships. P450 (16-HETE,HETEs are 18-HETE, created by 19-HETE, both the 20-HETE) lipoxygenase pathways (5-HETE, 12-HETE,with dihydroxyeicosatraenoic 15-HETE) and cytochrome acid P450 (DiHETE) (16-HETE, derived 18 from-HETE, EET 19 by-HETE, soluble 20 expoxide-HETE) pathways hydrolase. with dihydroxyeicosatraenoic20-carboxy-arachidonic acid acid (DiHETE) (20-COOH-AA) derived is a metabolitefrom EET ofby 20-HETE. soluble Eicosanoidsexpoxide hydrolase. that were 20- carboxysignificantly-arachidonic different acid in the (20 vitreous-COOH of- controlAA) is and a PDRmetabolite eyes in the of current 20-HETE. study areEicosanoids shown in bold that font were significantlyCOX = cyclooxygenase. different in the HETEs vitreous and of their control derivatives and PDR have eyes a role in in the pro-angiogenic current study processes are shown [17–28 in]. bold font COX = cyclooxygenase. HETEs and their derivatives have a role in pro-angiogenic processes [17– 15-HETE has been reported to be elevated in retinal samples of a mouse model of diabetes and 28]. ROP [17]. 15-HETE levels increase under hypoxic conditions [18–20], upregulate the expression of VEGF [21,22], and have pro-angiogenic effects that can be blocked by anti-VEGF antibodies [18–21,29]. Placenta15-HETE growth has been factor reported has also beento be implicated elevated inin triggeringretinal samples the 15-HETE of a mouse angiogenesis model pathway of diabetes [30]. and ROP15-HETE [17]. 15- hasHETE also levels been detected increase in under epiretinal hypoxic
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