Abstract
BackgroundTransforming growth factor type-β (TGF-β)/Smad pathway plays an essential role in vascular fibrosis. Reactive oxygen species (ROS) generation also mediates TGF-β signaling-induced vascular fibrosis, suggesting that some sort of interaction exists between Smad and redox pathways. However, the underlying molecular mechanism is largely unknown. This study aims to investigate the influence of poly(ADP-ribose) polymerase 1 (PARP1), a downstream effector of ROS, on TGF-β signaling transduction through Smad3 pathway in rat vascular smooth muscle cells (VSMCs).Methods and ResultsTGF-β1 treatment promoted PARP1 activation through induction of ROS generation in rat VSMCs. TGF-β1-induced phosphorylation and nuclear accumulation of Smad3 was prevented by treatment of cells with PARP inhibitor, 3-aminobenzamide (3AB) or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetami (PJ34), or PARP1 siRNA. TGF-β1 treatment promoted poly(ADP-ribosy)lation of Smad3 via activation of PARP1 in the nucleus. Poly(ADP-ribosy)lation enhanced Smad-Smad binding element (SBE) complex formation in nuclear extracts and increased DNA binding activity of Smad3. Pretreatment with 3AB, PJ34, or PARP1 siRNA prevented TGF-β1-induced Smad3 transactivation and expression of Smad3 target genes, including collagen Iα1, collagen IIIα1 and tissue inhibitor of metalloproteinase 1, in rat VSMCs.ConclusionsPARP1 is indispensable for TGF-β1 induced Smad3 activation in rat VSMCs. Targeting PARP1 may be a promising therapeutic approach against vascular diseases induced by dysregulation of TGF-β/Smad3 pathway.
Highlights
Transforming growth factor type-b (TGF-b)/Smad pathway is critical for maintaining normal vascular structure
poly(ADP-ribose) polymerase 1 (PARP1) is indispensable for TGF-b1 induced Smad3 activation in rat vascular smooth muscle cells (VSMCs)
Targeting PARP1 may be a promising therapeutic approach against vascular diseases induced by dysregulation of Transforming growth factor-b (TGF-b)/Smad3 pathway
Summary
Transforming growth factor type-b (TGF-b)/Smad pathway is critical for maintaining normal vascular structure. Besides RSmads, reactive oxygen species (ROS) mediate TGF-b signaling transduction; and inhibition of ROS generation effectively prevents TGF-b1induced over-production of collagens and tissue fibrosis [6,8,9]. These findings suggest that some sort of interaction exists between Smad and redox pathways in TGF-b signaling transduction. Reactive oxygen species (ROS) generation mediates TGF-b signaling-induced vascular fibrosis, suggesting that some sort of interaction exists between Smad and redox pathways. This study aims to investigate the influence of poly(ADP-ribose) polymerase 1 (PARP1), a downstream effector of ROS, on TGF-b signaling transduction through Smad pathway in rat vascular smooth muscle cells (VSMCs)
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