The cost to society of treating retinal neovascularization (NV) is high, and the economic and human cost of not treating retinopathy is even higher. We must develop effective inexpensive interventions. Although retinal vascular disease is characterized by dyslipidemia, there is limited research on lipid metabolism in retinopathy. We found a profound beneficial effect of a high ?3 vs. ?6 polyunsaturated fatty acid (PUFA) diet on retinal NV in oxygen-induced retinopathy (OIR);we propose to define the specific metabolites and enzymes involved. Retinopathy is characterized by inflammation and affects both retinal vessels and neurons. Lipids modulate inflammation and influence angiogenesis and neuroprotection. Potent pro-inflammatory and pro-angiogenic mediators are metabolized from ?6-PUFAs via cyclooxygenase (COX) and lipoxygenase (LOX). The same enzymes metabolize ?3-PUFAs into anti-inflammatory, anti-angiogenic, neuroprotective mediators. It is critical to understand the specific contributions of each of these major lipid metabolizing pathways and identify the metabolites that convey the respective effects of ?3 and ?6-PUFAs on retinopathy. Inhibitors or activators of the identified enzymes can then be used to specifically induce or enhance the beneficial effects observed with an ?3-PUFA replete diet. A third major PUFA metabolizing pathway, cytochrome P450s (Cyp450s) are implicated in vasodilation and inflammation. Little is known of CYP450 ?6 or ?3PUFA metabolite influence on NV or neuroprotection in retinopathy. Drugs modulating Cyp450s are in clinical trials for hypertension. We hypothesize that specific ?3 and ?6 PUFA metabolites, processed enzymatically from COX, LOX and Cyp450, mediate both vascular and neuronal homeostasis in OIR and diabetic retinopathy. Using COX1,2, LOX5,12/15 KO mice and Cyp450 endothelial specific trangenics on ?6 or ?3 PUFA diets in OIR we will (i) test if loss of a specific lipid enzyme suppresses or enhances the ?3 vs. ?6 PUFA protective effect on NV, identify the bioactive metabolites with lipidomics and the mechanisms by which they alter the severity of retinopathy with identification of lipid receptors (AIM I, II);and (ii) determine how lipid-derived pathways affect neurovascular crosstalk, vessel loss and regrowth in OIR and diabetic retinopathy (AIM III). SUMMARY: These studies will determine for retinopathy: i) the relative importance of ?3 vs. ?6 PUFA in diet (is eating ?3PUFA (fish) better than not eating ?6 PUFA (meat)?) ii) the positive and negative contributions of enzymatic pathway(s) that produce the major bioactive PUFA metabolites (does aspirin, a COX inhibitor or Zileuton, a LOX inhibitor, or a Cyp450 interactive drug negate eating fish if it blocks production of a beneficial metabolite? Is any metabolite a biomarker of increased or reduced disease risk?) iii) the effects of ?3/?6 PUFA on retinal neurons in OIR and diabetes (can an ?3 PUFA metabolite prevent neuron loss in diabetes?). Lipid biochemistry has been inadequately explored in this area although dyslipidemia is closely associated with progression of ocular vascular diseases. Dietary lipids may be safe, potent, and inexpensive treatment options.
We will examine the role of dietary lipids, processing enzymes and bioactive lipid metabolites in the pathogenesis of proliferative retinopathies;little work has been done in this area in stark contrast to the fact that diabetes, ROP and AMD have inflammatory components linked to lipid dysregulation and affected by lipid metabolites. We have previously found a profound beneficial effect of a high ?3 vs. ?6 polyunsaturated fatty acid (PUFA) diet on retinal neovascularization in oxygen-induced retinopathy (OIR). As PUFA tissue level is dependent on oral intake, (?3-PUFA is low in US diets), adjusting dietary lipids is a compelling way to prevent retinopathy.
|Lundgren, Pia; Hellgren, Gunnel; Pivodic, Aldina et al. (2018) Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity. Pediatr Res :|
|Nilsson, Anders K; Löfqvist, Chatarina; Najm, Svetlana et al. (2018) Long-chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation. Acta Paediatr 107:1020-1027|
|Stahl, Andreas; Krohne, Tim U; Eter, Nicole et al. (2018) Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr 172:278-286|
|Sun, Ye; Smith, Lois E H (2018) Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 4:101-122|
|Cakir, Bertan; Liegl, Raffael; Hellgren, Gunnel et al. (2018) Thrombocytopenia is associated with severe retinopathy of prematurity. JCI Insight 3:|
|Nilsson, Anders K; Löfqvist, Chatarina; Najm, Svetlana et al. (2018) Influence of Human Milk and Parenteral Lipid Emulsions on Serum Fatty Acid Profiles in Extremely Preterm Infants. JPEN J Parenter Enteral Nutr :|
|Fu, Zhongjie; Löfqvist, Chatarina A; Liegl, Raffael et al. (2018) Photoreceptor glucose metabolism determines normal retinal vascular growth. EMBO Mol Med 10:76-90|
|Löfqvist, Chatarina A; Najm, Svetlana; Hellgren, Gunnel et al. (2018) Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol 136:271-277|
|Lundgren, Pia; Hård, Anna-Lena; Wilde, Åsa et al. (2018) Implementing higher oxygen saturation targets reduced the impact of poor weight gain as a predictor for retinopathy of prematurity. Acta Paediatr 107:767-773|
|Bichsel, Colette A; Goss, Jeremy; Alomari, Mohammed et al. (2018) Association of Somatic GNAQ Mutation With Capillary Malformations in a Case of Choroidal Hemangioma. JAMA Ophthalmol :|
Showing the most recent 10 out of 108 publications