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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

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Abstract

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.

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Data availability

Any data and resources regarding this manuscript are available upon reasonable request from the corresponding authors (H.S.W.).

Abbreviations

ACSL4::

Acyl-Coenzyme A synthetase long-chain family member 4

AF::

Atrial fibrillation

BCA::

Bicinchoninic acid

CaM::

Calmodulin

DAPI::

4’, 6-Diamino-2-phenylindole

ECG::

Electrocardiogram

EtOH::

Ethanol

Fer-1::

Ferrostatin-1

FTH1::

Ferritin heavy chain 1

GPX4::

Glutathione peroxidase 4

GSH::

Glutathione

GSSG::

Glutathione disulfide

HO-1::

Heme oxygenase-1

HRP::

Horseradish peroxidase

Icar::

Icariin

LA::

Left atria

LVEF::

Left ventricular ejection fraction

LVFS::

Left ventricular fractional shortening

NCOA4::

Nuclear receptor coactivator 4

Nrf-2::

NFE2-related factor 2

PCD::

Programmed cell death

PLB::

Phospholamban

PTGS2::

Prostaglandin-endoperoxide synthase 2

ROS::

Reactive oxygen species

SIRT1::

Sirtuin 1

SLC7A11::

Solute carrier family 7 member 11

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Funding

This study is supported by the funds from the National Natural Science Foundation of China (82170328, 82070239), Shenyang Science and Technology Project (22–321-33–36) and Minsheng Science and Technology Plan of Liaoning Province (2021JH2/10300082, 2021JH2/10300062).

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Author notes

  1. Li-Ming Yu and Xue Dong have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, People’s Republic of China

    Li-Ming Yu, Tao Huang, Ji-Kai Zhao, Zi-Jun Zhou, Yu-Ting Huang, Yin-Li Xu, Qiu-Sheng Zhao, Zhi-Shang Wang, Hui Jiang, Zong-Tao Yin & Hui-Shan Wang

  2. The Third Outpatient Department, General Hospital of Northern Theater Command, 49 Beiling Road, Shenyang, Liaoning, 110032, People’s Republic of China

    Xue Dong

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  1. Li-Ming Yu
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Contributions

HSW, LMY and ZTY designed research; LMY performed research; LMY, XD, TH and ZJZ analyzed data; XD and LMY wrote the paper. JKZ, ZJZ, YTH, YLX, QSZ, ZSW and HJ helped to perform experiments, analyze data and revise the paper.

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Correspondence to Li-Ming Yu or Hui-Shan Wang.

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The animal studies were approved by the General Hospital of Northern Theatre Command Animal Care Committee. All experiments were carried out in accordance with institutional regulations and in adherence with the Guide for the Care and Use of Laboratory Animals issued by the US National Institutes of Health (NIH Publication, 8th Edition, 2011). Additionally, the study was reported in accordance with ARRIVE guidelines.

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Yu, LM., Dong, X., Huang, T. et al. Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1. Apoptosis 28, 607–626 (2023). https://doi.org/10.1007/s10495-023-01814-8

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