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Chalcone Flavokawain A Attenuates TGF-β1-induced Fibrotic Pathology via Inhibition of ROS/Smad3 Signaling Pathways and Induction of Nrf2/ARE-mediated Antioxidant Genes in Vascular Smooth Muscle Cells

Chalcone Flavokawain A Attenuates TGF-β1-induced Fibrotic Pathology via Inhibition of ROS/Smad3 Signaling Pathways and Induction of Nrf2/ARE-mediated Antioxidant Genes in Vascular Smooth Muscle Cells

You-Cheng Hseu, Ting-Yu Yang, Mei-Ling Li, Peramaiyan Rajendran, Dony Chacko Mathew, Chia-Hsuan Tsai, Ruei-Wan Lin, Chuan-Chen Lee, Hsin-Ling Yang

J Cell Mol Med. 2019 Feb;23(2):775-788.

PMID: 30549180

Abstract:

TGF-β1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Chalcones are reportedly cancer chemo-preventive food components that are rich in fruits and vegetables. In this study, flavokawain A (FKA, 2-30 μM), a naturally occurring chalcone in kava extracts, was evaluated for its anti-fibrotic and antioxidant properties in TGF-β1-stimulated vascular smooth muscle (A7r5) cells, as well as its underlying molecular mechanism of action. Immunofluorescence data showed down-regulated F-actin expression with FKA treatment in TGF-β1-stimulated A7r5 cells. Western blotting demonstrated that FKA treatment suppressed the expression of α-SMA and fibronectin proteins under TGF-β1 stimulation. Findings from wound-healing and invasion experiments showed that FKA inhibits TGF-β1-mediated migration and invasion. Western blotting demonstrated that treatment with FKA down-regulated MMP-9 and MMP-2 and up-regulated TIMP-1 expression. Further evidence showed that FKA decreased TGF-β1-mediated phosphorylation and the transcriptional activity of Smad3. TGF-β1-induced excessive ROS production was remarkably reversed by FKA treatment in A7r5 cells, and inhibition by FKA or N-acetylcysteine (NAC) substantially diminished TGF-β1-induced p-Smad3 activation and wound-healing migration. Interestingly, FKA-mediated antioxidant properties were associated with increased nuclear translocation of Nrf2 and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by the induction of HO-1, NQO-1 and γ-GCLC genes in FKA-treated A7r5 cells. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished the FKA-mediated antioxidant effects, indicating that FKA may inhibit TGF-β1-induced fibrosis through suppressing ROS generation in A7r5 cells. Our results suggested that anti-fibrotic and antioxidant activities of the chalcone flavokawain A may contribute to the development of food-based chemo-preventive drugs for fibrotic diseases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP37951136	Flavokawain A		37951-13-6	Price

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