Diabetic Stroke Severity: Epigenetic Remodeling and Neuronal, Glial, and Vascular Dysfunction.
Diabetic Stroke Severity: Epigenetic Remodeling and Neuronal, Glial, and Vascular Dysfunction.
复制标题
作者：
Kalani A;Kamat PK;Tyagi N
我们确定了1型糖尿病（T1 D）卒中（缺血-再灌注[IR]损伤）严重程度的机制，该机制影响与非糖尿病卒中相关的表观遗传学、神经元、神经胶质和脑血管成分相关的潜在标志物。该研究使用了雄性遗传T1 D Ins 2 +/−秋田和野生型（C57 BL/6 J）小鼠。实验小鼠组为1）假手术组、2）IR组、3）假秋田组和4）IRAkita组。小鼠大脑中动脉闭塞40 min，再灌注24 h。分析脑组织的炎症、神经胶质血管损伤、基质金属蛋白酶（MMP）-9表达和表观遗传学改变（DNA甲基转移酶-3a [DNMT-3a]; DNA甲基转移酶-1 [DNMT-1]; 5-甲基胞嘧啶[5-mC];和5-羟甲基胞嘧啶[5-hmC]）。颈动脉内异硫氰酸荧光素-BSA灌注用于测定软脑膜-小静脉通透性。与IR和假手术组相比，IRAkita小鼠表现出更多的梗死体积、水肿、炎症和血管MMP-9表达。与其他组相比，ShamAkita小鼠显示出最高的DNMT-1和DNMT-3a水平。与其他组相比，IRAkita小鼠紧密连接和粘附连接表达减少以及严重的小静脉渗漏例示了严重的脑血管损伤。有趣的是，我们发现与IR组相比，IRAkita中的表观遗传（5-mC，DNMT），血管（内皮型一氧化氮合酶），神经胶质（连接蛋白-43，神经胶质酸性蛋白，CD 11b）和神经元（神经元特异性烯醇化酶，神经元型一氧化氮合酶）标记物的差异调节（表达下调）。这些发现表明，IR损伤T1 D是更严重的，因为它加剧了差异表观遗传标记和神经胶质血管的变化相比，非糖尿病小鼠。
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) shamAkita, and 4) IRAkita. 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. IRAkita mice showed more infarct volume, edema, inflammation, and vascular MMP-9 expression compared with IR and sham groups. ShamAkita 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 IRAkita 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 IRAkita 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.