Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction.
Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction.
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DOI：
10.1038/labinvest.2010.89
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发表时间：
2010-09
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在糖尿病视网膜病变的发病机制中，视网膜线粒体功能失调，导致毛细血管细胞加速凋亡。基质金属蛋白酶 2 (MMP2) 被认为对于细胞完整性和细胞存活至关重要，糖尿病会激活视网膜及其毛细血管细胞中的 MMP2。本研究旨在阐明 MMP2 促进糖尿病视网膜病变发生的机制。使用分离的牛视网膜内皮细胞，评估了 MMP2（通过其 siRNA 和药理学抑制剂）对超氧化物积累和线粒体功能障碍的调节作用。在过表达线粒体超氧化物歧化酶的糖尿病小鼠中研究了抑制糖尿病诱导的视网膜超氧化物积累对 MMP2 及其调节因子的影响。抑制 MMP2 可改善葡萄糖诱导的线粒体超氧化物和膜通透性增加，防止细胞色素 c 从线粒体渗漏，并抑制毛细血管细胞凋亡。 MnSOD 的过度表达可保护视网膜免受糖尿病引起的 MMP2 及其膜激活剂 (MT1-MMP) 增加和组织激活剂 (TIMP-2) 减少的影响。这些结果表明，在糖尿病中，MMP2 通过线粒体功能障碍增加视网膜毛细血管细胞的膜通透性，从而激活视网膜毛细血管细胞的凋亡。了解 MMP2 在糖尿病视网膜病变发病机制中的作用应有助于为 MMP2 靶向治疗延缓糖尿病患者视网膜病变的发展奠定基础。
In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional resulting in accelerated apoptosis of its capillary cells. Matrix metalloproteinases2 (MMP2) is considered critical in the cell integrity and cell survival, and diabetes activates MMP2 in the retina and its capillary cells. The present study aims in elucidating the mechanism via which MMP2 contributes to the development of diabetic retinopathy. Using isolated bovine retinal endothelial cells, the effect of regulation of MMP2 (by its siRNA and pharmacological inhibitor) on superoxide accumulation and mitochondrial dysfunction was evaluated. Effect of inhibiting diabetes-induced retinal superoxide accumulation on MMP2 and its regulators was investigated in diabetic mice overexpressing mitochondrial superoxide dismutase. Inhibition of MMP2 ameliorated glucose-induced increase in mitochondrial superoxide and membrane permeability, prevented cytochrome c leakage from the mitochondria, and inhibited capillary cell apoptosis. Overexpression of MnSOD protected the retina from diabetes-induced increase in MMP2 and its membrane activator (MT1-MMP), and decrease in its tissue activator (TIMP-2). These results implicate that, in diabetes, MMP2 activates apoptosis of retinal capillary cells via mitochondrial dysfunction increasing their membrane permeability. Understanding the role of MMP2 in the pathogenesis of diabetic retinopathy should help lay ground for MMP2 targeted therapy to retard the development of retinopathy in diabetic patients.
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影响因子：
15.9
作者：
Mizutani, M;Kern, TS;Lorenzi, M
通讯作者：
Lorenzi, M
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
DOI：
10.1023/b:jobb.0000041755.22613.8d
发表时间：
2004-08-01
影响因子：
3
作者：
Dawson, VL;Dawson, TM
通讯作者：
Dawson, TM
影响因子：
3.1
作者：
Malemud, CJ
通讯作者：
Malemud, CJ
DOI：
10.1097/00006982-200102000-00005
发表时间：
2001-01-01
影响因子：
3.3
作者：
Jin, M;Kashiwagi, K;Tsukahara, S
通讯作者：
Tsukahara, S