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PCSK9 Inhibition Regulates Infarction-Induced Cardiac Myofibroblast Transdifferentiation via Notch1 Signaling

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Abstract

Increasing evidence suggests that PCSK9 inhibition protects cardiomyocytes against ischemia-reperfusion injury after myocardial infarction. However, it is not clear whether PCSK9 inhibitor (PCSK9i) affects cardiac fibroblasts (CFs) activation after MI. In this study we used SBC-115076, an antagonist of PCSK9, to investigate the role of PCSK9i in the conversion of CFs to cardiac myofibroblasts (CMFs) after MI and provided a basic for its clinical application in cardiac fibrosis after MI. In vivo study, PCSK9i was injected into mice 4 days after MI. Cardiac function and degree of fibrosis were evaluated by echocardiographic and tissue staining after treatment. Western blot showed that PCSK9i treatment decreases expression of α-SMA, collagen and increases expression of Notch1 in border infarct area. Vitro studies showed that PCSK9i decreased the degree of fibrosis, migration, and collagen fiber deposition in CFs. Confocal microscopy imaging also showed that hypoxia contributes to the formation of α-SMA stress filaments, and PCSK9i alleviated this state. Moreover, overexpression of Notch1 further suppress the activation of CFs under hypoxia. These results revealed that SBC-115076 ameliorates cardiac fibrosis and ventricular dysfunction post-myocardial infarction through inhibition of the differentiation of cardiac fibroblasts to myofibroblasts via Notch1/Hes1 signaling.

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Acknowledgements

The authors wish to thank all the investigators and supporters involved in this study.

Funding

This research was granted through the National Natural Science Foundation of China (grant no. 81974022) and Shanghai Municipal Health Commission (grant no. 201940206).

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Author notes

  1. These authors contributed equally: Chen Wu, Dawei Lin, Jian Ji, Yiweng Jiang

Authors and Affiliations

  1. Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chen Wu, Dawei Lin, Yiweng Jiang & Yaosheng Wang

  2. Department of Cardiology, Chongming Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China

    Jian Ji & Yaosheng Wang

  3. Clinical Research & Innovation Unit, Chongming Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China

    Feng Jiang

  4. Clinical Research & Innovation Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yaosheng Wang

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  1. Chen Wu
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  2. Dawei Lin
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  4. Yiweng Jiang
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  5. Feng Jiang
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Contributions

C.W.: writing - original draft; writing - review & editing, D.-w.L.: writing - original draft, writing - review & editing, J.J.: writing - original draft; data curation and analysis, Y.-w.J.: writing - original draft; data curation, F.J.: data analysis; project administration, Y.-s.W.: writing - review & editing, supervision, funding acquisition.

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Correspondence to Yaosheng Wang.

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Wu, C., Lin, D., Ji, J. et al. PCSK9 Inhibition Regulates Infarction-Induced Cardiac Myofibroblast Transdifferentiation via Notch1 Signaling. Cell Biochem Biophys 81, 359–369 (2023). https://doi.org/10.1007/s12013-023-01136-1

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  • DOI: https://doi.org/10.1007/s12013-023-01136-1

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