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Lefty1 Ameliorates Post-infarction Fibrosis by Suppressing p-Smad2 and p-ERK1/2 Signaling Pathways

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Abstract

Transforming growth factor-β1 signaling pathways are known to involve in the development of post-infarction fibrosis, a process characterized by the aberrant activation, proliferation, and differentiation of fibroblasts, as well as the unbalanced turnover of extracellular matrix proteins. Recent studies have shown that Lefty1, a novel member of TGF-β superfamily, acts as a brake on the TGF-β signaling pathway in non-cardiac tissues. However, its role in myocardial infarction (MI)–induced fibrosis and left ventricular remodeling has not been fully elucidated. Here, for the first time, we reported that Lefty1 alleviated post-MI fibroblast proliferation, differentiation, and secretion through suppressing p-Smad2 and p-ERK1/2 signaling pathways in vivo and in vitro. In MI mice or TGF-β1-treated neonatal rat cardiac fibroblasts (CFBs), the expression of Lefty1 was upregulated. Adenovirus-mediated overexpression of Lefty1 significantly attenuated TGF-β1-induced CFBs’ proliferation, differentiation, and collagen production. Using the adeno-associated virus approach, we confirmed that Lefty1 attenuates MI-induced cardiac injury, as evidenced by the decreased infarct size and preserved cardiac function. These results highlight the importance of Lefty1 in the prevention of post-MI fibrosis and may help identify potential targets for therapeutic intervention of cardiac fibrosis.

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Abbreviations

TGF-β1:

Transforming growth factor-β1

MI:

Myocardial infarction

CFB:

Cardiac fibroblast

CF:

Cardiac fibrosis

ECM:

Extracellular matrix

HF:

Heart failure

ALK:

Activin receptor–like kinase

Smad:

Small mother against decapentaplegic

MAPK:

Mitogen-activated protein kinase

PI3K:

Phosphoinositide 3-kinase

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

EMT:

Epithelial-mesenchymal transition

UUO:

Unilateral ureteral obstruction

rAAV9:

Recombinant adeno-associated virus serotype 9

GFP:

Green fluorescent protein

PBS:

Phosphate buffered saline

DMEM:

Dulbecco’s modified Eagle’s medium

α-SMA:

α-smooth muscle actin

MTT:

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

OD:

Optical density

LVSD:

LV end-systolic diameter

LVDD:

End-diastolic diameter

EF:

Ejection fraction

FS:

Fractional shortening

BMP:

Bone morphogenetic protein

GDF:

Growth differentiation factor

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Funding

This study was supported by Grants from the National Natural Science Foundation of China (No. 81700271) and S&T Program of Hebei (No. H2018105054).

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Author notes

  1. Changyi Li and Jingrui 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

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

  2. Laboratory of Molecular Biology, Head and Neck Surgery, Tangshan Gongren Hospital, No. 27, Wenhua Road, Lubei District, Tangshan, 063000, China

    Chang-yi Li & Wan-ning Hu

  3. Department of Respiratory Medicine, Tangshan People’s Hospital, Tangshan, China

    Xin-xin Li

  4. Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Lei Zhao

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

    Hui Xi

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  1. Chang-yi Li
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Correspondence to Wan-ning Hu or Song-nan Li.

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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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Associate Editor Junjie Xiao oversaw the review of this article.

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Li, Cy., Zhang, Jr., Li, Xx. et al. Lefty1 Ameliorates Post-infarction Fibrosis by Suppressing p-Smad2 and p-ERK1/2 Signaling Pathways. J. of Cardiovasc. Trans. Res. 14, 636–646 (2021). https://doi.org/10.1007/s12265-020-10089-2

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  • DOI: https://doi.org/10.1007/s12265-020-10089-2

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