The Natural Flavone Acacetin Confers Cardiomyocyte Protection Against Hypoxia/Reoxygenation Injury Via AMPK-Mediated Activation of Nrf2 Signaling Pathway

Overview

Journal Front Pharmacol

Date 2018 Jun 6

PMID 29867499

Citations 35

Authors

Wei-Yin Wu

Yun-Da Li

Yu-Kai Cui

Chan Wu

Yi-Xiang Hong

Gang Li

Yao Wu

Ling-Jun Jie

Yan Wang

Gui-Rong Li

Affiliations

Soon will be listed here.

Abstract

The present study investigates the potential signal pathway of acacetin in cardioprotection against ischemia/reperfusion injury using an hypoxia/reoxygenation model in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts. It was found that acacetin (0.3-3 μM) significantly decreased the apoptosis and reactive oxygen species production induced by hypoxia/reoxygenation injury in cardiomyocytes and H9C2 cardiomyoblasts via reducing the pro-apoptotic proteins Bax and cleaved-caspase-3 and increasing the anti-apoptotic protein Bcl-2. In addition, acacetin not only suppressed the release of pro-inflammatory cytokines TLR-4 and IL-6 induced by hypoxia/reoxygenation injury, but also increased the secretion of anti-inflammatory cytokine IL-10. Moreover, acacetin increased Nrf2 and HO-1 in a concentration-dependent manner, and rescued SOD1 and SOD2 reduction induced by hypoxia/reoxygenation insult. These beneficial effects of acacetin disappeared in cells with silenced Nrf2, suggesting that Nrf2 activation participates in the cardioprotective effect of acacetin against hypoxia/reoxygenation insult. However, acacetin-induced Nrf2 activation was not observed in cells with silenced AMPK and in ventricular tissues of rat hearts treated with the AMPK inhibitor Compound C and subjected to ischemia/reperfusion injury. Our results demonstrate for the first time that AMPK-mediated Nrf2 activation is involved in the cardiomyocytes protection of acacetin against hypoxia/reoxygenation injury by activating a series of intracellular signals involved in anti-oxidation, anti-inflammation, and anti-apoptosis.

Citing Articles

SS-31 modification alleviates ferroptosis induced by superparamagnetic iron oxide nanoparticles in hypoxia/reoxygenation cardiomyocytes.

Lu Q, Yao X, Zheng H, Ou J, You J, Zhang Q Heliyon. 2024; 10(20):e38584.

PMID: 39506934 PMC: 11538732. DOI: 10.1016/j.heliyon.2024.e38584.

Acacetin protects against acute lung injury by upregulating SIRT1/ NF-κB pathway.

Gu L, Yin Y, Liu M, Yu L Heliyon. 2024; 10(17):e37083.

PMID: 39296097 PMC: 11409107. DOI: 10.1016/j.heliyon.2024.e37083.

Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia.

Chen L, Du Y, Hu Y, Li X, Chen Y, Cheng Y Transl Psychiatry. 2024; 14(1):267.

PMID: 38951484 PMC: 11217384. DOI: 10.1038/s41398-024-02984-y.

Acacetin inhibits inflammation by blocking MAPK/NF-κB pathways and NLRP3 inflammasome activation.

Bu J, Mahan Y, Zhang S, Wu X, Zhang X, Zhou L Front Pharmacol. 2024; 15:1286546.

PMID: 38389927 PMC: 10883387. DOI: 10.3389/fphar.2024.1286546.

Nrf2-mediated therapeutic effects of dietary flavones in different diseases.

Huang W, Zhong Y, Gao B, Zheng B, Liu Y Front Pharmacol. 2023; 14:1240433.

PMID: 37767395 PMC: 10520786. DOI: 10.3389/fphar.2023.1240433.

References

Murphy E, Steenbergen C . Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008; 88(2):581-609. PMC: 3199571. DOI: 10.1152/physrev.00024.2007. View

Markowski P, Boehm O, Goelz L, Haesner A, Ehrentraut H, Bauerfeld K . Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation. Basic Res Cardiol. 2013; 108(5):376. PMC: 3778842. DOI: 10.1007/s00395-013-0376-7. View

Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X . Nrf2-a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke. Mol Neurobiol. 2016; 54(8):6006-6017. DOI: 10.1007/s12035-016-0111-0. View

Li C, Zhang W, Frei B . Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. Redox Biol. 2016; 9:104-113. PMC: 4961307. DOI: 10.1016/j.redox.2016.06.006. View

Tamaki N, Orihuela-Campos R, Inagaki Y, Fukui M, Nagata T, Ito H . Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model. Free Radic Biol Med. 2014; 75:222-9. DOI: 10.1016/j.freeradbiomed.2014.07.034. View

Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y . An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236(2):313-22. DOI: 10.1006/bbrc.1997.6943. View

Hausenloy D, Yellon D . Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol. 2016; 13(4):193-209. DOI: 10.1038/nrcardio.2016.5. View

Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T . Myocardial ischemia reperfusion injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth. 2012; 16(3):123-32. PMC: 3457795. DOI: 10.1177/1089253211436350. View

Ma Q . Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013; 53:401-26. PMC: 4680839. DOI: 10.1146/annurev-pharmtox-011112-140320. View

10.

Cody V . Crystal and molecular structures of flavonoids. Prog Clin Biol Res. 1988; 280:29-44. View

11.

Xing Y, Niu T, Wang W, Li J, Li S, Janicki J . Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2. PLoS One. 2012; 7(9):e44899. PMC: 3444497. DOI: 10.1371/journal.pone.0044899. View

12.

Wang Y, Wang Y, Li G . TRPC1/TRPC3 channels mediate lysophosphatidylcholine-induced apoptosis in cultured human coronary artery smooth muscles cells. Oncotarget. 2016; 7(32):50937-50951. PMC: 5239449. DOI: 10.18632/oncotarget.10853. View

13.

Li J, Zhang C, Xing Y, Janicki J, Yamamoto M, Wang X . Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. Cardiovasc Res. 2011; 90(2):315-24. DOI: 10.1093/cvr/cvr010. View

14.

Lv H, Liu Q, Wen Z, Feng H, Deng X, Ci X . Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol. 2017; 12:311-324. PMC: 5345976. DOI: 10.1016/j.redox.2017.03.001. View

15.

Xu X, Li M, Chen W, Yu H, Yang Y, Hang L . Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway. Oxid Med Cell Longev. 2016; 2016:4378461. PMC: 5021875. DOI: 10.1155/2016/4378461. View

16.

Liou C, Wu S, Chen L, Yeh K, Chen C, Huang W . Acacetin from Traditionally Used Kar. et Kir. Suppressed Adipogenesis in 3T3-L1 Adipocytes and Attenuated Lipid Accumulation in Obese Mice. Front Pharmacol. 2017; 8:589. PMC: 5581916. DOI: 10.3389/fphar.2017.00589. View

17.

Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel J . Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999; 13(1):76-86. PMC: 316370. DOI: 10.1101/gad.13.1.76. View

18.

Zhong Z, Tang Y . Upregulation of Periostin Prevents High Glucose-Induced Mitochondrial Apoptosis in Human Umbilical Vein Endothelial Cells via Activation of Nrf2/HO-1 Signaling. Cell Physiol Biochem. 2016; 39(1):71-80. DOI: 10.1159/000445606. View

19.

Hayyan M, Hashim M, AlNashef I . Superoxide Ion: Generation and Chemical Implications. Chem Rev. 2016; 116(5):3029-85. DOI: 10.1021/acs.chemrev.5b00407. View

20.

Li G, Wang Y, Li G . Bradykinin regulates cell growth and migration in cultured human cardiac c-Kit+ progenitor cells. Oncotarget. 2017; 8(7):10822-10835. PMC: 5355226. DOI: 10.18632/oncotarget.14609. View