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Up-regulation of Nrf2/HO-1 and inhibition of TGF-β1/Smad2/3 signaling axis by daphnetin alleviates transverse aortic constriction-induced cardiac remodeling in mice.
- Source :
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Free radical biology & medicine [Free Radic Biol Med] 2022 Jun; Vol. 186, pp. 17-30. Date of Electronic Publication: 2022 May 02. - Publication Year :
- 2022
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Abstract
- Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-β1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang-II)-stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-β1/Smad2/3 signaling axis.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Subjects :
- Angiotensin II metabolism
Animals
Cardiomegaly drug therapy
Cardiomegaly metabolism
Collagen metabolism
Mice
Reactive Oxygen Species metabolism
Signal Transduction drug effects
Up-Regulation
Ventricular Remodeling drug effects
Heme Oxygenase-1 metabolism
Membrane Proteins metabolism
NF-E2-Related Factor 2 metabolism
Smad2 Protein antagonists & inhibitors
Smad2 Protein metabolism
Smad3 Protein antagonists & inhibitors
Smad3 Protein metabolism
Transforming Growth Factor beta1 antagonists & inhibitors
Transforming Growth Factor beta1 metabolism
Umbelliferones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 186
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35513128
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2022.04.019