The Unconventional Role of Acid Sphingomyelinase in Regulation of Retinal Microangiopathy in Diabetic Human and Animal Models

Abstract

OBJECTIVEAcid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study.RESEARCH DESIGN AND METHODSProtein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies.RESULTSWe identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolae-associated ASM, prevents a tumor necrosis factor-α–induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM−/− mice or inhibition of ASM activity by DHA prevents acellular capillary formation.CONCLUSIONSThis is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy.

Loss of Caveolin-1 Impairs Retinal Function Due to Disturbance of Subretinal Microenvironment

“…1. We note that Cav-1 immunoreactivity is also prominent in retinal and choroidal vasculature, as expected, based on several reports of Cav-1 and caveolae in retinal vascular endothelium and pericytes (40,41,43,77,78). Both Müller glial (71) and RPE (72) cells play critical roles in maintaining the retinal environment by regulating active transport properties and blood-retinal barrier functions.…”

Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD

“…33,34 Becker et al discovered that ceramide production in the lungs contributed to inflammatory cytokine production during cystic fibrosis, 35 and amitriptyline reduced ceramide production, inflammatory cytokine production, and inflammatory cell recruitment in a mouse model of cystic fibrosis. 35,36 Other studies have shown that SMase-mediated ceramide synthesis in plasma membranes promotes microvessel formation.…”

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.…”