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Sacubitril/Valsartan Decreases Atrial Fibrillation Susceptibility by Inhibiting Angiotensin II-Induced Atrial Fibrosis Through p-Smad2/3, p-JNK, and p-p38 Signaling Pathways

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Abstract

Sacubitril/valsartan (SAC/VAL) prevents angiotensin II (AngII) from binding AT1-R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Our study provided evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. After 28 days of AngII continuous subcutaneous stimulation, rats in SAC/VAL group exhibited reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts, and decreased susceptibility to AF. We further found that inhibition of p-Smad2/3, p-JNK, and p-p38MAPK pathways is involved in the role of SAC/VAL on AngII-induced atrial fibrosis in vivo. These results emphasize the importance of SAC/VAL in the prevention of AngII-induced atrial fibrosis and may help to enrich the options for AF pharmacotherapy.

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Abbreviations

α-SMA:

α-smooth muscle actin

SAC/VAL:

sacubitril/valsartan

AT-R:

angiotensin receptor

ACEIs:

angiotensin-converting enzyme inhibitors

AF:

atrial fibrillation

AFB:

atrial fibroblast

AngII:

angiotensin II

ANP:

atrial natriuretic peptide

ARBs:

angiotensin receptor blockers

BNP:

B-type natriuretic peptide

CNP:

C-type natriuretic peptide

DBP:

diastolic blood pressure

EF:

ejection fraction

ELISA:

enzyme-linked immunosorbent assay

EPS:

electrophysiological study

ERK:

extracellular signal-regulated kinase

HFrEF:

heart failure with reduced ejection fraction

IHC:

immunohistochemistry

JNK:

C-Jun N-terminal kinase

LAD:

left atrial diameter

LVDD:

LV end-diastolic diameter

MAPK:

mitogen-activated protein kinase

MBP:

mean blood pressure

MI:

myocardial infarction

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MV E/A:

mitral valvular early and atrial peaks

NEP:

neutral endopeptidase

NFAT:

calcineurin/nuclear factor of activated T cell

NF-κB:

nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3:

nucleotide-binding oligomerization domain-like receptor protein 3

NPs:

natriuretic peptides

NT-proBNP:

N-terminal pro-brain natriuretic peptide

p-CaMKII:

phosphorylated expression calmodulin-dependent protein kinase II

PKG:

protein kinase G

RAAS:

renin-angiotensin-aldosterone system

SBP:

systolic blood pressure

Smad:

small mother against decapentaplegic

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Funding

This study was supported by Grants from the National Natural Science Foundation of China (Nos. 81700271), S&T Program of Hebei (Nos. H2018105054).

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Author notes

  1. Song-nan Li and Jing-rui Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No. 2, Anzhen Road, Chao Yang District, Beijing, 100029, China

    Song-nan Li, Jing-rui Zhang, Lu Zhou & Chang-yi Li

  2. Department of Cardiology, Peking University International Hospital, Beijing, China

    Hui Xi

  3. Department of Radiololgy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Lei Zhao

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  1. Song-nan Li
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  2. Jing-rui Zhang
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  3. Lu Zhou
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  4. Hui Xi
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  5. Chang-yi Li
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  6. Lei Zhao
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Contributions

Chang-yi Li, Song-nan Li, and Lei Zhao conceived and planned the experiments. Song-nan Li, Jing-rui Zhang, and Hui Xi carried out the experiments. Song-nan Li, Chang-yi Li, and Lei Zhao contributed to the interpretation of the results. Song-nan Li and Jing-rui Zhang took the lead in writing the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Chang-yi Li or Lei Zhao.

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All experimental procedures were conducted in compliance with both the Animal Care and Use Committee of Capital Medical University and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (the 8th Edition, NRC 2011). This article does not contain any studies with human participants performed by any of the authors.

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The authors declare no competing interests.

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Associate Editor Nicola Smart oversaw the review of this article

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Li, Sn., Zhang, Jr., Zhou, L. et al. Sacubitril/Valsartan Decreases Atrial Fibrillation Susceptibility by Inhibiting Angiotensin II-Induced Atrial Fibrosis Through p-Smad2/3, p-JNK, and p-p38 Signaling Pathways. J. of Cardiovasc. Trans. Res. 15, 131–142 (2022). https://doi.org/10.1007/s12265-021-10137-5

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