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Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.

Titel:	Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.
Autor/in / Beteiligte Person:	Yu, LM ; Dong, X ; Huang, T ; Zhao, JK ; Zhou, ZJ ; Huang, YT ; Xu, YL ; Zhao, QS ; Wang, ZS ; Jiang, H ; Yin, ZT ; Wang, HS
Link:	Zum Volltext
Zeitschrift:	Apoptosis : an international journal on programmed cell death, Jg. 28 (2023-04-01), Heft 3-4, S. 607-626
Veröffentlichung:	2005- : Dordrecht, Netherlands : Springer ; <i>Original Publication</i>: London : Rapid Science Publishers,, 2023
Medientyp:	academicJournal
ISSN:	1573-675X (electronic)
DOI:	10.1007/s10495-023-01814-8
Schlagwort:	Animals Apoptosis Sirtuin 1 genetics Tumor Suppressor Protein p53 Ethanol toxicity Atrial Fibrillation chemically induced Atrial Fibrillation drug therapy Ferroptosis Atrial Remodeling
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Apoptosis] 2023 Apr; Vol. 28 (3-4), pp. 607-626. <i>Date of Electronic Publication: </i>2023 Jan 28. MeSH Terms: Atrial Fibrillation* / chemically induced ; Atrial Fibrillation* / drug therapy ; Ferroptosis* ; Atrial Remodeling* ; Animals ; Apoptosis ; Sirtuin 1 / genetics ; Tumor Suppressor Protein p53 ; Ethanol / toxicity References: Nattel S, Heijman J, Zhou L, Dobrev D (2020) Molecular basis of atrial fibrillation pathophysiology and therapy: a translational perspective. Circ Res 127:51–72. 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Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.