Regulation of Myofibroblast Differentiation by Poly(ADP-Ribose) Polymerase 1

• Published in: The American journal of pathology Vol. 182; no. 1; pp. 71 - 83
• Main Authors: Hu, Biao, Wu, Zhe, Hergert, Polla, Henke, Craig A., Bitterman, Peter B., Phan, Sem H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013; American Society for Investigative Pathology
• Subjects: Actins - genetics; Actins - metabolism; Animals; Bleomycin; Cell Differentiation - genetics; Cell Differentiation - physiology; Cells, Cultured; CpG Islands - genetics; DNA Methylation; Female; Gene Expression Regulation - physiology; Gene Silencing; Lung - cytology; Lung - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts - cytology; Myofibroblasts - enzymology; Myofibroblasts - pathology; Pathology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - deficiency; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - physiology; Protein Processing, Post-Translational - physiology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Rats; Rats, Inbred F344; Regular; Smad3 Protein - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2012.09.004

Poly(ADP-ribosyl)ation (PARylation) is a post-translational protein modification effected by enzymes belonging to the poly(ADP-ribose) polymerase (PARP) superfamily, mainly by PARP-1. The key acceptors of poly(ADP-ribose) include PARP-1 itself, histones, DNA repair proteins, and transcription factors. Because many of these factors are involved in the regulation of myofibroblast differentiation, we examined the role of PARylation on myofibroblast differentiation. Overexpression of PARP-1 with an expression plasmid activated expression of the α-SMA gene (Acta2), a marker of myofibroblast differentiation in lung fibroblasts. Suppression of PARP-1 activity or gene expression with PARP-1 inhibitors or siRNA, respectively, had the opposite effect on these cells. PARP-1–deficient cells also had reduced α-SMA gene expression. DNA pyrosequencing identified hypermethylated regions of the α-SMA gene in PARP-1–deficient cells, relative to wild-type cells. Interestingly, and of potential relevance to human idiopathic pulmonary fibrosis, PARP activity in lung fibroblasts isolated from idiopathic pulmonary fibrosis patients was significantly higher than that in cells isolated from control subjects. Furthermore, PARP-1–deficient mice exhibited reduced pulmonary fibrosis in response to bleomycin-induced lung injury, relative to wild-type controls. These results suggest that PARylation is important for myofibroblast differentiation and the pathogenesis of pulmonary fibrosis.