title: Diabetic Stroke Severity: Epigenetic Remodeling and Neuronal, Glial, and Vascular Dysfunction.
abstract: We determined the mechanism of severity during type 1 diabetic (T1D) stroke (ischemia-reperfusion [IR] injury) that affects potential markers associated with epigenetics, neuronal, glial, and vascular components of the brain with regard to nondiabetic stroke. The study used male genetic T1D Ins2(+/-) Akita and wild-type (C57BL/6J) mice. The experimental mice groups were 1) sham, 2) IR, 3) sham(Akita), and 4) IR(Akita). Mice were subjected to middle cerebral artery occlusion for 40 min, followed by reperfusion for 24 h. Brain tissues were analyzed for inflammation, neuro-glio-vascular impairments, matrix metalloproteinase (MMP)-9 expression, and epigenetic alterations (DNA methyltransferase-3a [DNMT-3a]; DNA methyltransferase-1 [DNMT-1]; 5-methylcytosine [5-mC]; and 5-hydroxymethylcytosine [5-hmC]). Intracarotid fluorescein isothiocyanate-BSA infusion was used to determine pial-venular permeability. IR(Akita) mice showed more infarct volume, edema, inflammation, and vascular MMP-9 expression compared with IR and sham groups. Sham(Akita) mice showed the highest DNMT-1 and DNMT-3a levels compared with the other groups. Reduced tight and adherent junction expressions and severe venular leakage exemplified intense cerebrovascular impairment in IR(Akita) mice compared with the other groups. Interestingly, we found differential regulations (downregulated expression) of epigenetic (5-mC, DNMTs), vascular (endothelial nitric oxide synthase), glial (connexin-43, glial fibrillary acidic protein, CD11b), and neuronal (neuron-specific enolase, neuronal nitric oxide synthase) markers in IR(Akita) compared with the IR group. These findings suggest that IR injury in T1D is more severe because it intensifies differential epigenetic markers and neuro-glio-vascular changes compared with nondiabetic mice.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalani
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY.
authors.forename: Pradip Kumar
authors.initials: PK
authors.lastname: Kamat
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY n0tyag01@louisville.edu.
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology; D002199:Capillary Permeability; D016923:Cell Death; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D003925:Diabetic Angiopathies / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D044127:Epigenesis, Genetic; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020521:Stroke / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D066253:Vascular Remodeling
chemical_list: D015415:Biomarkers; C000715535:Dnmt3a protein, mouse; D009419:Nerve Tissue Proteins; D019001:Nitric Oxide Synthase; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse