Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis.
Diabetes mellitus aggravates hemorrhagic transformation after ischemic stroke via mitochondrial defects leading to endothelial apoptosis.
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DOI：
10.1371/journal.pone.0103818
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hara H
中科院分区：
文献类型：
--
作者：
Mishiro K;Imai T;Sugitani S;Kitashoji A;Suzuki Y;Takagi T;Chen H;Oumi Y;Tsuruma K;Shimazawa M;Hara H
糖尿病是中风的关键风险因素，与中风频率增加和预后不良有关。尽管内皮功能障碍是卒中的一个已知因素，但其潜在的机制尚未阐明。本研究的目的是阐明慢性高血糖可能导致卒中后预后恶化的机制，尤其是线粒体的改变。观察高血糖对链脲佐菌素(STZ)诱导的糖尿病小鼠大脑中动脉闭塞(MCAO)后24小时出血性转化的影响。我们还检测了高糖暴露6天对人脑微血管内皮细胞(HBMVECs)和诱导多能干细胞来源的人内皮细胞(icell内皮细胞)的细胞死亡、线粒体功能和形态的影响。高血糖加重卒中后出血性转化，但不加重脑梗塞。高糖暴露可增加HBMVECs的凋亡率、Capase-3活性、凋亡诱导因子(AIF)和细胞色素c的释放，并影响线粒体功能(细胞增殖、ATP含量、线粒体膜电位，增加基质金属蛋白酶(MMPs)-9活性，但不影响活性氧的产生)。此外，在糖尿病细胞中观察到线粒体的形态异常(大量碎裂、空泡化和嵴断裂)。在iCell内皮细胞中也发现了类似的现象。结论：慢性高血糖通过线粒体功能障碍和形态改变，部分通过激活基质金属蛋白酶-9，导致糖尿病小鼠血管内皮细胞caspase依赖性的凋亡，从而加重了卒中后的出血性转化。线粒体靶向治疗可能是未来糖尿病并发症的一种临床创新治疗策略。
Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO) in streptozotocin (STZ) -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs) or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells). Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF) and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP)-9 activity, but not reactive oxygen species production). Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption). A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.
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影响因子：
8.2
作者：
Makino, A.;Scott, B. T.;Dillmann, W. H.
通讯作者：
Dillmann, W. H.
影响因子：
9.3
作者：
Kageyama S;Yokoo H;Tomita K;Kageyama-Yahara N;Uchimido R;Matsuda N;Yamamoto S;Hattori Y
通讯作者：
Hattori Y
影响因子：
8.2
作者：
Hawkins, B. T.;Lundeen, T. F.;Egleton, R. D.
通讯作者：
Egleton, R. D.
高血糖通过活性氮介导的 Jun N 末端激酶激活诱导胰岛内皮细胞凋亡
DOI：
10.1016/j.bbamcr.2011.03.011
发表时间：
2011-06-01
影响因子：
5.1
作者：
Gong, Lei;Liu, Fu-qiang;Zhang, Ming-Xiang
通讯作者：
Zhang, Ming-Xiang
DOI：
10.1073/pnas.94.5.2007
发表时间：
1997-03-04
影响因子：
11.1
作者：
Hara, H;Friedlander, RM;Moskowitz, MA
通讯作者：
Moskowitz, MA