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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Role of PARP-1 as a novel transcriptional regulator of MMP-9 in diabetic retinopathy
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Role of PARP-1 as a novel transcriptional regulator of MMP-9 in diabetic retinopathy

机译：PARP-1作为糖尿病视网膜病变中MMP-9的新型转录调节剂的作用

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摘要

In diabetes, matrix metalloproteinase-9 (MMP-9) is activated, which damages mitochondria, resulting in accelerated capillary cell apoptosis. Regulation of MMP-9 is controlled by multiple transcription factors including nuclear factor-kB (NF-kB) and activator protein-1 (AP-1). Binding of these transcription factors, however, can be regulated by poly(ADP-ribose) polymerase-1 (PARP-1), which forms a strong initiation complex at the promoter region and facilitates multiple rounds of gene transcription. This complex formation with the transcription factors is regulated by posttranslational acetylation of PARP-1, and in diabetes, the deacetylating enzyme, Sirtl, is inhibited. Our aim was to understand the role of PARP-1 in transcriptional regulation of MMP-9 in the development of diabetic retinopathy. Using human retinal endothelial cells, the effect of PARP-1 inhibition (pharmacologically by PJ34, 1 mu M; or genetically by its siRNA) on MMP-9 expression was investigated. The effect of PARP-1 acetylation on its binding at the MMP-9 promoter, and with NF-kB/AP-1, was investigated in the cells transfected with SirtI. In vitro results were validated in the retinal microvessels from diabetic mice either administered PJ34, or overexpressing Sirtl. Inhibition of PARP-1 ameliorated hyperglycemia-induced increase in the binding of NF-kB/AP-1 at the MMP-9 promoter, decreased MMP-9 expression and ameliorated mitochondrial damage. Overexpression of Sirtl attenuated diabetes-induced increase in PARP-1 binding at MMP-9 promoter or with NF-kB/AP-1. Thus, PARP-1, via manipulating the binding of NF-kB/AP-1 at the MMP-9 promoter, regulates MMP-9 expression, which helps maintain mitochondrial homeostasis.
机译：在糖尿病中，激活基质金属蛋白酶-9（MMP-9），其损害线粒体，导致毛细胞细胞凋亡加速。 MMP-9的调节由包括核因子-Kb（NF-KB）和活化剂蛋白-1（AP-1）的多种转录因子控制。然而，这些转录因子的结合可以由聚（ADP-核糖）聚合酶-1（PARP-1）调节，其在启动子区形成强烈的开始复合物，并促进多轮基因转录。这种复杂的形成因子通过PARP-1的后翻译乙酰化而调节，并且在糖尿病中，抑制脱乙酰酶Sirtl。我们的目标是了解PARP-1在糖尿病视网膜病变发育中MMP-9转录调节中的作用。使用人类视网膜内皮细胞，研究了PARP-1抑制的影响（PJ34，1μm;或通过其siRNA的遗传学）对MMP-9表达的影响。在用Sirti转染的细胞中研究了PARP-1乙酰化对其在MMP-9启动子的结合和NF-KB / AP-1的影响。在糖尿病小鼠中，在视网膜微血管中验证了体外结果，可以施用PJ34，或过表达Sirtl。 PARP-1改善的高血糖诱导的NF-KB / AP-1在MMP-9启动子的结合增加的抑制降低了MMP-9表达和改善的线粒体损伤。 Sirtl的过度表达减毒糖尿病诱导的PARP-1在MMP-9启动子或NF-KB / AP-1结合增加。因此，PARP-1通过操纵MMP-9启动子的NF-KB / AP-1的结合来调节MMP-9表达，这有助于保持线粒体稳态。

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