Novel Role of Mitochondrial Matrix Metalloproteinase-2 in the Development of Diabetic Retinopathy
Novel Role of Mitochondrial Matrix Metalloproteinase-2 in the Development of Diabetic Retinopathy
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DOI：
10.1167/iovs.10-6368
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发表时间：
2011-05-01
影响因子：
4.4
通讯作者：
Kowluru, Renu A.
中科院分区：
文献类型：
--
作者：
Mohammad, Ghulam;Kowluru, Renu A.
目的。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，DNA受损，毛细血管细胞加速凋亡。基质金属蛋白酶-2 (MMP2) 被激活并促进凋亡，抑制糖尿病视网膜病变发展的疗法可减轻 MMP2 的激活。作者试图阐明激活的 MMP2 导致线粒体功能障碍的可能机制。方法。在视网膜内皮细胞中研究了 MMP2 调节对线粒体功能障碍的影响以及对线粒体完整性很重要的分子伴侣 (Hsp60) 和间隙连接蛋白连接蛋白 43 的亚细胞定位。该结果在从过度表达 MnSOD 的糖尿病小鼠中分离的视网膜线粒体以及接受玻璃体内施用 MMP2 的正常大鼠的视网膜中得到证实。高葡萄糖会增加视网膜内皮细胞线粒体中的 MMP2 并减少连接蛋白 43。虽然Hsp60基因转录本增加，但其在线粒体中的丰度减少，并且与MMP2的相互作用增加。在小鼠中，MnSOD 的过度表达可保护视网膜线粒体免受糖尿病引起的 MMP2 增加以及 Hsp60 和连接蛋白 43 减少的影响。正常大鼠中施用 MMP2 会损伤视网膜线粒体，减少 Hsp60 和连接蛋白 43，并加速视网膜毛细血管细胞的凋亡。结论。线粒体中升高的 MMP2 通过调节 Hsp60 和破坏连接蛋白 43 来降解其膜，从而激活细胞凋亡机制。更好地了解 MMP2 介导的线粒体损伤可能有助于确定治疗这种致盲性疾病的新策略。 （投资眼科可见科学。2011 年；52：3832-3841）DOI：10.1167/iovs.10-6368
PURPOSE. In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional, their DNA is damaged, and capillary cells undergo accelerated apoptosis. Matrix metalloproteinase-2 (MMP2) becomes activated and proapoptotic, and the therapies that inhibit the development of diabetic retinopathy alleviate MMP2 activation. The authors sought to elucidate the possible mechanism by which activated MMP2 contributes to mitochondrial dysfunction.METHODS. The effect of the regulation of MMP2 on mitochondrial dysfunction and the subcellular localization of the molecular chaperone important for mitochondrial integrity (Hsp60) and gap junction protein connexin 43 were investigated in retinal endothelial cells. The results were confirmed in retinal mitochondria isolated from diabetic mouse overexpressing MnSOD and in the retinas of normal rats that received intravitreal administration of MMP2.RESULTS. High glucose increased MMP2 and decreased connexin 43 in the mitochondria of retinal endothelial cells. Although the Hsp60 gene transcript was increased, its abundance in the mitochondria was decreased, and its interaction with MMP2 was increased. In mice, the overexpression of MnSOD protected retinal mitochondria from diabetes-induced increases in MMP2 and decreases in Hsp60 and connexin 43. MMP2 administration in normal rats damaged the retinal mitochondria, decreased Hsp60 and connexin 43, and accelerated the apoptosis of retinal capillary cells.CONCLUSIONS. Elevated MMP2 in the mitochondria degrades its membranes by modulating Hsp60 and damaging connexin 43, and this activates the apoptotic machinery. Better understanding of MMP2-mediated mitochondrial damage could help identify new strategies for the treatment of this blinding disease. (Invest Ophthalmol Vis Sci. 2011; 52: 3832-3841) DOI: 10.1167/iovs.10-6368