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Jie Fan, Jian Liu, Craig E Crosson; Crosstalk between Sphingolipids and HDACs in the Development of Ischemic Retinal Injury. Invest. Ophthalmol. Vis. Sci. 2017;58(8):247.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies have shown that elevations in acid sphingomyelinase and histone deacetylase (HDAC) activities contribute to ischemic and ocular hypertensive retinal injury. However, how or if these pathways interact remain unknown. This study investigates the interaction between sphingolipid metabolism and protein acetylation in the sequela of events that mediate ischemic retinal injury.
The effects of acute ischemic retinal injury on the activities of acid sphingomyelinase (ASMase) and Class I HDACs, ceramide and TNF-α levels, and retinal function (ERGs) were evaluated in ASMase+/- knockout and wild type (WT) mice. Studies utilized primary human optic nerve head astrocyte cultures treated with C2-ceramide (from 0.1μM to 10μM) for 6 hours to analyze changes in Class I HDAC activity and TNF-α secretion.
In WT mice, ischemic injury produced a rapid (1 to 2 hrs post-injury) and significant increase in retinal Class I HDAC and ASMase activity of 26.7 ± 2.9% and 29.8 ± 2.6%, respectively. We also measured significant elevation in retinal levels of ceramides (2.1 fold) and TNF-α (3.2 fold). Seven days post-injury, these increases were associated with significant reduction in ERG a- and b-wave amplitudes. In ASMase+/- mice, the ischemic-induced increases in Class I HDAC and ASMase activity were significantly suppressed by 71% and 88% when compared to WT mice. The level of ceramides and TNF-α were significantly decreased by 45% and 46% when compared to corresponding WT retinas. At 7 days post-injury, ASMase+/- mice exhibited significant improvement in a- and b-wave amplitudes when compared to corresponding WT mice. In astrocytes treated with C2-ceramide, Class I HDAC activity and the secreted levels of TNF-α increased in a concentration-dependent manner when compared with vehicle treated cells.
These results provide initial evidence that ischemia-induced increases in Class I HDAC activity and TNF-α secretion are largely dependent on increased sphingolipids metabolism, and ASMase is a participates in this response. Together these data support the idea that sphingolipid metabolism plays a central role in initiating retinal responses to ischemic injury.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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