Effect of Acid Sphingomyelinase on Membrane Fluidity in Circulating Angiogenic Cells: Implications for Diabetic Retinopathy
Gallimore, Jacob T.
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Diabetic hyperglycemia and dyslipidemia affect the retinal blood vessels in diabetic patients, causing 65% of afflicted patients to develop diabetic retinopathy. The diabetic metabolic insult leading to retinal vascular degeneration is proposed to involve retinal endothelial cell damage, that is then inadequately repaired due to compromised availability and functionality of circulating angiogenic cells (CACs). The central hypothesis of this research is that CACs become “trapped” in the diabetic bone marrow due to reduced deformability and are unable to migrate to, extravasate and home to the retinal sight of injury. Acid sphingomyelinase (ASMase) is responsible for the hydrolysis of sphingomyelin to ceramide and has been shown to be upregulated in diabetic patients. We propose that an increased level of ASMase in diabetic patients increases ceramide levels, thus decreasing cell membrane fluidity, leading to reduce deformability of diabetic CACs. To measure the effect of ASMase on membrane fluidity, CACs from ASMase-/-, wild type (WT), and diabetic mice were examined utilizing time-resolved fluorescence decay measurements of the chromophore perylene embedded in live cells. ASMase WT mice displayed a statistically significant decrease in membrane fluidity compared to the ASMase-/- (p < 0.05) and diabetic mice had a significantly less fluid membrane than WT mice (p < 0.05). This data supports the hypothesis that upregulation of ASMase in diabetic patients could contribute to the deformability of the CACs and provide potential areas of focus for diabetes retinopathy research. Future work will focus both on improving the methodology, and measuring membrane fluidity in both healthy and diabetic human CACs.