N-3 Polyunsaturated Fatty Acids Prevent Diabetic Retinopathy by Inhibition of Retinal Vascular Damage and Enhanced Endothelial Progenitor Cell Reparative Function

Abstract

ObjectiveThe vasodegenerative phase of diabetic retinopathy is characterized by not only retinal vascular degeneration but also inadequate vascular repair due to compromised bone marrow derived endothelial progenitor cells (EPCs). We propose that n-3 polyunsaturated fatty acid (PUFA) deficiency in diabetes results in activation of the central enzyme of sphingolipid metabolism, acid sphingomyelinase (ASM) and that ASM represents a molecular metabolic link connecting the initial damage in the retina and the dysfunction of EPCs.Research Design and MethodsType 2 diabetic rats on control or docosahexaenoic acid (DHA)-rich diet were studied. The number of acellular capillaries in the retinas was assessed by trypsin digest. mRNA levels of interleukin (IL)-1β, IL-6, intracellular adhesion molecule (ICAM)-1 in the retinas from diabetic animals were compared to controls and ASM protein was assessed by western analysis. EPCs were isolated from blood and bone marrow and their numbers and ability to form colonies in vitro, ASM activity and lipid profiles were determined.ResultsDHA-rich diet prevented diabetes-induced increase in the number of retinal acellular capillaries and significantly enhanced the life span of type 2 diabetic animals. DHA-rich diet blocked upregulation of ASM and other inflammatory markers in diabetic retina and prevented the increase in ASM activity in EPCs, normalized the numbers of circulating EPCs and improved EPC colony formation.ConclusionsIn a type 2 diabetes animal model, DHA-rich diet fully prevented retinal vascular pathology through inhibition of ASM in both retina and EPCs, leading to a concomitant suppression of retinal inflammation and correction of EPC number and function.

Diabetes Mellitus and Ischemic Diseases

“…Interestingly, DHA-rich diet fully prevents retinal vascular pathology, leading to a concomitant suppression of tissue inflammation and correction of EPC number and function. 97,98 Finally, endothelial cells not only are inert conduits delivering metabolites and oxygen but also establish a vascular niche that orchestrates regeneration and healing. Hence, a recent and elegant study uncovers that in response to liver injury, differential recruitment of proregenerative CXCR7-Id1 transcription factor versus profibrotic fibroblast growth factor 2 receptor type 1-CXCR4 angiocrine pathways balances regeneration and fibrosis.…”

A monophasic extraction strategy for the simultaneous lipidome analysis of polar and nonpolar retina lipids

“…including diabetic retinopathy (8)(9)(10)(11)(12), Stargardt-like macular dystrophy ( 13 ), age-related macular degeneration ( 14 ), Smith-Lemli-Opitz syndrome ( 15 ), and retinopathy of prematurity ( 16 ). In some retinal disorders, particularly diabetic retinopathy, all of these metabolic defects may be present simultaneously (8)(9)(10)(11)(12).…”

“…In some retinal disorders, particularly diabetic retinopathy, all of these metabolic defects may be present simultaneously (8)(9)(10)(11)(12). Unfortunately, analysis of structurally diverse lipid species such as sphingolipids, fatty acids, and phospholipids that span a wide range of polarities, degree of unsaturation, and abundance within a given tissue remains analytically prohibitive, particularly given the small amount of retinal tissue that may be obtained when using rodent models of retinal disease.…”

Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think? A Perspective from the Residual Risk Reduction Initiative (R3i)

“…There may be a rationale for investigating the potential of omega-3 fatty acids, given experimental data showing favorable effects on key mechanisms implicated in the vasodegenerative phase of diabetic retinopathy, and preservation of retinal function in animal models of type 2 diabetes mellitus [54,55]. Additionally, expression of GPR109A, a niacin receptor, which has anti-inflammatory activity in the retinal pigment epithelium, is increased in diabetic mouse and human retinas, which might suggest therapeutic potential [56].…”