The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina

Abstract

In this work we advance the hypothesis that omega-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. ω-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology.

How is ω-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary ω-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases.

What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, ω-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-α (PPAR-α) and the retinoid X receptor. In the case of PPAR-α, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production.

Research on model systems demonstrates that ω-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)—specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFκB). NFκB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that ω-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.

Introduction

Long-chain polyunsaturated fatty acids (LCPUFAs) demonstrate anti-angiogenic, anti-vasoproliferative, and neuroprotective actions on factors and processes implicated in the pathogenesis of proliferative and degenerative retinal diseases. Many retinal diseases of public health significance manifest tissue and cellular dysfunction in the forms of abnormal angiogenesis, proliferative neovascularization, excessive vascular permeability, immunoregulatory dysfunction, alterations in physiologic reduction-oxidation (redox) balance, or neuronal/retinal pigment epithelial (RPE) cell degeneration. A number of bioactive molecules within the eye affect, and are effected by, such conditions. These molecules are activated in response to ischemia, light exposure, oxygen/energy metabolism and oxidative stress, apoptosis, cell signaling pathways, inflammation, and developmental processes associated with aging. They operate within complex systems and include eicosanoids, angiogenic factors, matrix metalloproteinases (MMPs), reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. Effects and actions of metabolic and environmental bioactivators and bioactive molecules include activation of phospholipase A₂ (PLA₂), cyclooxgenase (COX), and lipoxygenase (LOX). Activation of this enzyme system yields a pool of LCPUFAs and bioactive eicosanoids.

Omega-3 (ω-3) LCPUFAs demonstrate the capacity to modulate production, activation, and potency of bioactive molecules. In some cases these LCPUFAs operate as lipid–protein complexes via signaling cascades in nuclear and cytosolic compartments. In others, they affect substrate pools or availability of biosynthetic enzymes. They influence gene expression as ligands to a number of transcription factors and act as endocannabinoid autocoids. Docosahexaenoic acid (DHA, C22:6ω-3), a major dietary ω-3 LCPUFA, is also a major structural lipid in sensory and vascular retina. Metabolic and dietary DHA insufficiency is associated with alterations in visual system structure and function. DHA and its substrate, eicosapentaenoic acid (EPA, C20:5ω-3), influence eicosanoid metabolism by reducing ω-6 LCPUFA levels (mainly arachidonic acid (C20:4ω-6, AA)) and competing for enzymes (COX and LOX) used to produce AA-based angiogenic and proinflammatory series 2- and 4-eicosanoids.

In this work we present the body evidence implicating LCPUFAs as key modulators of processes influencing retinal health and disease. Section 2 contains a general overview of properties, functions, and actions of LCPUFAs; a more detailed treatment of the issue appears in Chow (2000). Section 3 contains an overview of LCPUFA metabolism, intake, transport, and accretion to the retina; additional information exists in Neuringer (1993), Salem et al. (2001), and Bazan et al. (1993). In Section 4 we consider actions of LCPUFAs on biochemical and biophysical processes that define properties of retinal membranes and signaling systems. Section 5 contains information on metabolic and environmental factors and processes that activate molecules driving retinal neovascularization and neural cell death. These bioactivating factors include ischemia, chronic light exposure, cellular redox balance, cell death, inflammation, neuroactive signaling molecules, and the aging process. In Section 6 we consider the role of LCPUFAs in the structure and function of the vascular retina. In Section 7 we consider the means by which ω-3 LCPUFAs may operate as protective factors in retinal diseases that manifest vascular and neural pathology; we present three examples: diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). These diseases were selected on the basis of life-span risk, the burden they exert on society, and the coexistence of vascular and neural degenerative pathologies. Our general conclusion is that there is consistent evidence to suggest that ω-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, or age-associated retinal diseases. Section conclusions are displayed in Table 1.