Purchase this article with an account.
Oday Alsarraf, Jie Fan, Phillip W Yates, Craig E Crosson; Histone Deacetylases in Retinal Injury and Ischemic Preconditioning. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2177.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The increase in histone deacetylase (HDAC) activity and resulting dysregulation of protein acetylation is an integral event in retinal degenerations associated with ischemia and ocular hypertension. The current studies investigate the role of individual HDAC isoforms and acetylation status in ischemic retinal injury.
Rat eyes were unilaterally subjected to retinal injury by 45 minutes of acute ischemia, and retinal neuroprotection induced by 5 minutes of an ischemic preconditioning (IPC) event, 24 hours prior to injury. Isolated rat retinas were evaluated for protein acetylation and HDAC expression by Western blotting, and HDAC activity by a class-specific fluorometric enzymatic assay with selective isoform inhibitors. HDAC retinal localization was determined by immunohistochemistry. Morphometric and electroretinogram (ERG) analyses were used to assess differences in retinal structure and function seven days following ischemic injury.
In control eyes, analysis of class I isoforms demonstrated that HDAC1/2 accounted for 32.1 ±4.5%, and HDAC3 for 65.6 ±2.1%, of total activity. Following ischemia, total class I HDAC activity increased by 18.9%, and this increase resulted solely from a rise in HDAC1/2 activity. No change in HDAC3 activity was measured. Activity of class II HDACs and HDAC8 was negligible. Compared to control eyes at 24 hours post-ischemia, retinal protein acetylation was significantly reduced by 39.4%. No change in HDAC proteins were detected by Western blot analysis. Immunohistochemistry demonstrated that HDAC1 and 2 are localized in the inner retinal layers. In control animals 7 days post ischemia, ERG a- and b-waves amplitudes were significantly reduced by 23 and 41%, respectively. Histologic examination demonstrated extensive degeneration of inner retinal layers. In rats receiving an IPC stimulus, the ischemia-induced decline in ERG a- and b-wave amplitudes were blocked and retina morphology preserved. IPC also suppressed the rise in class I HDAC activity and normalized the protein acetylation status in the retina.
Although multiple HDACs are detected in the retina, these studies provide evidence that hypoacetylation associated with ischemic injury results from the selective rise in HDAC1/2 activity and that neuroprotection induced by IPC is mediated in part by suppressing HDAC activity.
This PDF is available to Subscribers Only