Abstract 194: Epigenetic And Neuro-glia-vascular Alternations After Stroke In Type-1 Diabetes
Background and Purpose: Diabetes is a major risk factor for ischemic cerebrovascular disease that increases morbidity and mortality in type-1 diabetes mellitus (T1DM) population. The undefined mechanism for diabetic stroke severity delayed the therapeutic options to deal with this clinically relevant problem. Therefore, the purpose of this study was to determine the mechanism of severity during diabetic stroke by observing epigenetic, neuro-glia-vascular components of the brain with regard to non-diabetic stroke.
Methods: To test this hypothesis we employed 8-10 weeks old male diabetic Ins2+/- Akita (genetic T1DM) and wild type mice. The experimental mice groups were: 1) sham, 2) IR, 3) shamAkita, and 4) IRAkita. Mice were subjected to ischemic injury (40 min) followed by reperfusion for 24 h. Infarct area was measured with TTC. The brain tissues were analyzed for inflammation, glial, neuronal, vascular, MMP-9 expressions and global epigenetic alterations (5-methylcytosine, 5-mC and 5-hydroxymethylcytosine, 5-hmC). Intra-carotid FITC-BSA infusion was used to evaluate venular leakage.
Results: Diabetic IRAkita mice showed more infarct, edema, inflammation, and vascular MMP-9 expressions as compared to non-diabetic and sham mice groups (p<0.05). Intense vascular impairment was determined by reduced expressions of the vascular junctions in IR-injured diabetic mice as compared to other mice groups (p<0.01). FITC-BSA infusion exemplified severe venular leakage in diabetic mice as compared to other experimental mice (F=3, 103, p<0.01). Interestingly, we also found differential regulation of epigenetic [5-hmC; (F=3, 236.8, p<0.01)], vascular [eNOS (F=3, 74.98, p<0.01)], glial [Cx43 (F=3, 37.24, p<0.01); GFAP (F=3, 40.48, p<0.01); CD11b (F=3, 18.36, p<0.01)], and neuronal [NSE (F=3, 292.2, p<0.01); nNOS (F=3, 116.8, p<0.01)] markers in IR-injured diabetic mice as compared to non-diabetic mice.
Conclusion: We conclude that IR-injury during T1DM exhibits intense inflammation, cellular injury and BBB dysfunction leading to worse stroke outcomes. The data also indicate that severity in IR-injured T1DM mice might be amplified by differential epigenetic and neuro-glio-vascular cascades. This work was supported by NIH grant HL107640.
Author Disclosures: A. Kalani: None. P.K. Kamat: None. N. Tyagi: None.
- © 2015 by American Heart Association, Inc.