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Proprotein convertase subtilisin/kexin 9 inhibitor downregulates microRNA-130a-3p expression in hepatocytes to alleviates atherosclerosis progression

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Abstract

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been shown to regulate lipid metabolism and reduce the risk of cardiovascular events. This study explores the effect and potential mechanism of PCSK9 inhibitors on lipid metabolism and coronary atherosclerosis. HepG2 cells were incubated with PCSK9 inhibitor. ApoE-/- mice were fed with a high fat to construct an atherosclerosis model, and then treated with PCSK9 inhibitor (8 mg/kg for 8 w). PCSK9 inhibitor downregulated microRNA (miRNA)-130a-3p expression in a dose-dependent manner. And, miR-130a-3p could bind directly to the 3' untranslated region (3'-UTR) region of LDLR to down-regulate LDLR expression in HepG2 cells, as confirmed by the luciferase reporter gene assay. In addition, miR-130a-3p overexpression significantly attenuated the promoting effect of PCSK9 inhibitor on LDLR and DiI-LDL uptake in HepG2 cells. More importantly, in vivo experiments confirmed that PCSK9 inhibitor could significantly inhibit miR-130a-3p levels and promote LDLR expression in liver tissues, thus regulating serum lipid profile and alleviating the progression of coronary atherosclerosis. PCSK9 inhibitor could moderately improve coronary atherosclerosis by regulating miR-130a-3p/LDLR axis, providing an exploitable strategy for the treatment of coronary atherosclerosis.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was funded by the Science and Technology Plan Projects of Tianjin Jinnan district (No. 20190104) and Tianjin Key Medical Discipline(specialty) Construction Project [Internal Medicine (Cardiology):TJYXZDXK-055B].

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Authors and Affiliations

  1. The Department of Cardiology, Tianjin Chest Hospital, No. 261, Taierzhuang South Road, Jinnan District, Tianjin, 300222, China

    Jinghan Xu, Chuyi Han, Tingting Li, Dongxia Jin, Fumei Zhao & Hongliang Cong

  2. The Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China

    Jinghan Xu, Chuyi Han, Tingting Li, Dongxia Jin, Fumei Zhao & Hongliang Cong

  3. Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, China

    Jinghan Xu, Chuyi Han, Tingting Li, Dongxia Jin, Fumei Zhao & Hongliang Cong

  4. TianJin Institute of Cardiovascular Diseases, Tianjin, China

    Jinghan Xu, Chuyi Han, Tingting Li, Dongxia Jin, Fumei Zhao & Hongliang Cong

  5. Internal Medicine, Tianjin Jinnan Hospital, Tianjin, China

    Junrong Zuo

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  1. Jinghan Xu
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Contributions

J.X. and J.Z. wrote the main manuscript text. C.H. and T.L. prepared Figs. 1, 2 and 3. J.Z. and F.Z. prepared Figs. 4 and 5. J.X., D.J. and H.C. prepared Fig. 6. All authors reviewed the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Hongliang Cong.

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The authors declare no competing interests.

Ethics approval

All experiments were approved and conducted by the ethics committee of Tianjin Chest Hospital (TJCH-2021-009).

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Xu, J., Zuo, J., Han, C. et al. Proprotein convertase subtilisin/kexin 9 inhibitor downregulates microRNA-130a-3p expression in hepatocytes to alleviates atherosclerosis progression. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1727–1736 (2024). https://doi.org/10.1007/s00210-023-02708-x

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