High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.
High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.
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DOI：
10.1016/j.bbrc.2013.09.086
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发表时间：
2013-10-18
影响因子：
3.1
通讯作者：
Price, Tulin O.
中科院分区：
文献类型：
--
作者：
Shah, Gul N.;Morofuji, Yoichi;Banks, William A.;Price, Tulin O.
关键词：
高血糖诱导的氧化应激导致糖尿病对脑微血管系统的损害。靠近脑微血管内皮细胞的周细胞对血脑屏障的完整性至关重要，特别容易受到氧化应激的影响。根据我们最近发表的结果，糖尿病12周后，链脲佐菌素-糖尿病小鼠脑组织出现氧化应激和周细胞疏松，高糖培养的脑周细胞出现细胞内氧化应激和细胞凋亡。糖尿病的氧化应激被认为是由高血糖诱导的葡萄糖氧化代谢(呼吸)增强过程中产生的活性氧物种(ROS)引起的。为了验证这一假设，我们研究了高糖对小鼠脑周细胞呼吸频率和ROS产生的影响。在此之前，我们已经证明，对线粒体碳酸氢酶的药理抑制可以保护大脑免受氧化应激和周细胞丢失的影响。高糖诱导的周细胞氧化应激和细胞凋亡也可通过抑制线粒体碳酸酐酶而逆转。因此，我们扩展了我们目前的研究，以确定这些抑制剂对高糖诱导的周细胞呼吸和ROS增加的影响。我们现在报道，在高糖挑战下，周细胞的呼吸和ROS都显著增加。此外，线粒体碳酸氢酶的抑制显著减缓了呼吸和ROS的产生。这些数据提供了新的证据，证明已经在临床上使用的线粒体碳酸酐酶的药理抑制剂在保护大脑免受氧化应激方面是有益的，这些氧化应激是高血糖诱导的呼吸增强所产生的ROS的结果。
Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.
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DOI：
10.1016/s0921-8777(99)00026-9
发表时间：
1999-07-30
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
LeDoux, SP;Driggers, WJ;Wilson, GL
通讯作者：
Wilson, GL
影响因子：
7.7
作者：
Nakamura, S;Makita, Z;Koike, T
通讯作者：
Koike, T
影响因子：
7.7
作者：
Nerlich, AG;Sauer, U;Schleicher, ED
通讯作者：
Schleicher, ED
影响因子：
--
作者：
Luchsinger, Jose A.;Reitz, Christiane;Mayeux, Richard
通讯作者：
Mayeux, Richard
影响因子：
5.1
作者：
Nishimura, C;Hotta, Y;Saito, T
通讯作者：
Saito, T