Role of PARP-1 as a novel transcriptional regulator of MMP-9 in diabetic retinopathy.

Role of PARP-1 as a novel transcriptional regulator of MMP-9 in diabetic retinopathy. Biochim Biophys Acta. 2017 May 03;: Authors: Mishra M, Kowluru RA Abstract 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, Sirt1, 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, 1μM; or genetically by its siRNA) on MMP-9 expression was investigated. The effect of PARP-1 acetylation on PARP-1 binding at the MMP-9 promoter, and with NF-kB/AP-1, was investigated in the cells transfected with Sirt1. In vitro results were validated in the retinal microvessels from diabetic mice either administered PJ34, or overexpressing Sirt1. Inhibition of PARP-1 ameliorated hyper...
Source: Biochimica et Biophysica Acta - Category: Biochemistry Authors: Tags: Biochim Biophys Acta Source Type: research