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Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression

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Abstract

Background

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported.

Methods and Results

We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro.

Conclusion

Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.

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Data Availability

All relevant data are within the paper.

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Funding

We acknowledge the Nanjing Health Science and Technology development special project fund (YKK19074) for supporting completion of this study. Juan Zhang is the grant recipient and one of the corresponding authors in this manuscript.

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Author notes

  1. Peng Ye and Xiao-Min Jiang contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu, China

    Peng Ye, Xiao-Min Jiang, Wei-Chun Qian & Juan Zhang

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  1. Peng Ye
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  2. Xiao-Min Jiang
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Contributions

YP performed the immunoblot analyses, analyzed the echo data, and drafted the manuscript. JXM and QWC performed the mouse work, including feeding and coordinating the echography and harvest dates and times. YP and JXM aided in harvesting the mice and analyzing the data. ZJ designed and oversaw the study, and edited the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Juan Zhang.

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Ethics Approval

This study was approved by the Institutional Animal Care and Use Committee of Nanjing Medical University and was conducted under the Guidelines for The Care and Use of Laboratory Animals (National Research Council).

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Informed consent was obtained from all individual participants included in the study.

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Written informed consent for publication was obtained from all participants.

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The authors declare that there are no known conflicts of interest associated with this publication, and no significant financial support was received for this work that could have influenced its outcome.

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Ye, P., Jiang, XM., Qian, WC. et al. Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07458-9

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