Abstract W P85: Enzymes that Influence Histone Acetylation and DNA Methylation are Altered Following Ischemia in an Age and Sex Specific Manner
Background: In animal models, ischemia results in larger infarcts in middle-aged females as compared to young adult females and several measures important for stroke recovery are impaired in middle-aged animals including growth factor production and neuroinflammatory responses. Middle-aged males however, appear to be similar to their younger counterparts on these measures. This impaired recovery following stroke may be related to epigenetic alterations that occur during aging, including changes in DNA methylation and histone acetylation. The level of acetylation is modulated in part by histone deacetylases (HDACs); whereas DNA methylation is modulated by DNA methyltransferases. We evaluated the hypothesis that ischemia would result in epigenetic alterations and that both sex and age would influence this epigenetic profile.
Methods: The middle cerebral artery was occluded in adult (6 month) and middle-aged (11+ month) male and female Sprague Dawley rats (n=8/grp). Nuclear proteins were extracted from the ischemic and non-ischemic hemispheres 48 hours after surgery. ELISA based assays were used to measure the amount of HDAC 6 and DNA methyltransferase 1 (DNMT1) as well as the activity of sirtuins and pan-HDACs.
Results: Following stroke, the ischemic hemisphere had higher levels of HDAC activity (.22±.02 vs .16±.008; p<.05) and a greater amount of HDAC 6 (76.6±5.1 vs 43.3±1.6; p<.05) than the non-ischemic hemisphere. In contrast, sirtuin activity was lower in the ischemic hemisphere (4.9±.5 vs 7.4±.6; p<.05). Importantly, middle-aged males had lower levels of sirtuin activity than adult males (4.7±.4 vs 8.3±.9; p<.05). DNMT1 did not differ between the hemispheres; however, middle-aged females had a greater amount of DNMT1 than adult females (239.6±45.8 vs 125.3±19.8; p<.05).
Conclusions: Epigenetic modifications are known to influence gene transcription and this study suggests that ischemia alters the activity and availability of enzymes that modulate DNA methylation and histone deacetylation. Importantly, the effects of ischemia are sex and age specific. The differences in epigenetic profiles between the sexes and during aging provide insights into possible mechanisms for the differences in stroke recovery previously documented.
Author Disclosures: N.C. Chisholm: None. M. Henderson: None. F. Sohrabji: None.
- © 2014 by American Heart Association, Inc.