PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

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Abstract

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) belongs to an intracellular invertase or decarboxylase and is an independent risk factor for atherosclerosis (AS). This study aimed to investigate the therapeutic potential of the PCSK9 inhibitor, inclisiran, and its underlying mechanism in AS.

Methods

ApoE ^-/- mice were fed with a high-fat diet (HFD) and intraperitoneally injected with 1, 5, or 10 mg/kg inclisiran. Low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels were determined using commercially available kits. Oil Red O staining was applied to detect the aortic plaque area and oil formation. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to induce cell injuries. Cell death was determined using a Hoechst 33342/propidium iodide (PI) dual-staining assay. Cytotoxicity was measured by lactate dehydrogenase (LDH) activity analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses were performed to examine the pyroptosis-related factors.

Results

Inclisiran inhibited the levels of LDL-C, TC, and TG, but increased the HDL-C level in the AS animal model. It also significantly inhibited plaque and oil droplet formation in a dose-dependent manner. Moreover, inclisiran markedly inhibited pyroptosis, as evidenced by the decreased levels of cleaved-caspase-1, NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC), gasdermin-D (GSDMD)-N, interleukin (IL)-1β, and IL-18. Furthermore, inclisiran substantially inhibited cell death and cytotoxicity induced by ox-LDL in HUVECs.

Conclusions

Inclisiran exerted an anti-atherosclerotic effect by inhibiting pyroptosis. This study provides a theoretical basis for the therapeutic potential of inclisiran in AS.

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Most cited references 37

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Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Marc Sabatine, Robert Giugliano, Anthony Keech … (2017)

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.

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The changing landscape of atherosclerosis

Peter Libby (2021)

Emerging evidence has spurred a considerable evolution of concepts relating to atherosclerosis, and has called into question many previous notions. Here I review this evidence, and discuss its implications for understanding of atherosclerosis. The risk of developing atherosclerosis is no longer concentrated in Western countries, and it is instead involved in the majority of deaths worldwide. Atherosclerosis now affects younger people, and more women and individuals from a diverse range of ethnic backgrounds, than was formerly the case. The risk factor profile has shifted as levels of low-density lipoprotein (LDL) cholesterol, blood pressure and smoking have decreased. Recent research has challenged the protective effects of high-density lipoprotein, and now focuses on triglyceride-rich lipoproteins in addition to low-density lipoprotein as causal in atherosclerosis. Non-traditional drivers of atherosclerosis-such as disturbed sleep, physical inactivity, the microbiome, air pollution and environmental stress-have also gained attention. Inflammatory pathways and leukocytes link traditional and emerging risk factors alike to the altered behaviour of arterial wall cells. Probing the pathogenesis of atherosclerosis has highlighted the role of the bone marrow: somatic mutations in stem cells can cause clonal haematopoiesis, which represents a previously unrecognized but common and potent age-related contributor to the risk of developing cardiovascular disease. Characterizations of the mechanisms that underpin thrombotic complications of atherosclerosis have evolved beyond the 'vulnerable plaque' concept. These advances in our understanding of the biology of atherosclerosis have opened avenues to therapeutic interventions that promise to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.

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Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Kausik K Ray, R Wright, David Kallend … (2020)

Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Print and electronic): November 2022

Publication date (Print): November 2022

Volume: 10

Issue: 22

Electronic Location Identifier: 1205

Affiliations

[1 ]deptSchool of Pharmacy , Naval Medical University , Shanghai, China;

[2 ]deptBasic Medical School , Qingdao University , Qingdao, China;

[3 ]deptSchool of Pharmacy , Guangzhou Medical University , Guangzhou, China;

[4 ]Department of Immunopharmacology, Jining Medical University, Rizhao , China

Author notes

Contributions: (I) Conception and design: N Kong; (II) Administrative support: N Kong; (III) Provision of study materials or patients: N Kong, Q Xu, W Cui; (IV) Collection and assembly of data: X Feng, H Gao; (V) Data analysis and interpretation: H Gao; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Huijie Gao. Department of Immunopharmacology, Jining Medical University, No. 669, Xueyuan Road, Donggang District, Rizhao, China. Email: gaohuijie2019@ 123456163.com ; Ni Kong. School of Pharmacy, Naval Medical University, No. 325, Guohe Road, Yangpu District, Shanghai, China. Email: koni69689@ 123456tom.com or Kongni0113@ 123456163.com .

Article

Publisher ID: atm-10-22-1205

DOI: 10.21037/atm-22-4652

PMC ID: 9761140

PubMed ID: 36544639

SO-VID: dcadfa82-1db0-4c09-8a6f-c3d6b9c1e74f

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

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Abstract

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Most cited references 37

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

The changing landscape of atherosclerosis

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

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