2. Academic Validation
  3. Inclisiran inhibits oxidized low-density lipoprotein-induced foam cell formation in Raw264.7 macrophages via activating the PPARγ pathway

Inclisiran inhibits oxidized low-density lipoprotein-induced foam cell formation in Raw264.7 macrophages via activating the PPARγ pathway

  • Autoimmunity. 2022 Jun;55(4):223-232. doi: 10.1080/08916934.2022.2051142.
Zhaoping Wang 1,  Xiangyu Chen 2,  Jingxing Liu 3,  Yingcui Wang 4,  Suhua Zhang 5
Affiliations

Affiliations

  • 1 Department of Emergency, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P.R. China.
  • 2 Department of Emergency, Weihai Municipal Hospital, Weihai, P.R. China.
  • 3 Emergency Department, Qingdao Municipal Hospital (Group), Qingdao NO.9 People's Hospital, Qingdao, P.R. China.
  • 4 Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P.R. China.
  • 5 Department of Geriatrics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P.R. China.
PMID: 35289693 DOI: 10.1080/08916934.2022.2051142
Abstract

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a well-known proprotein convertase that influences foam cell formation and modulates atherosclerosis. Inclisiran is a novel chemosynthetic small interfering RNA that inhibits PCSK9 synthesis. This study aimed to explore the effect of inclisiran on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation in Raw264.7 macrophages and to investigate the underlying mechanisms. Raw264.7 cells were treated with ox-LDL to induce the formation of macrophage-derived foam cells. Oil Red O staining and high-performance liquid chromatography were performed to detect lipid accumulation and Cholesterol levels. Dil-ox-LDL uptake assay, CCK-8, RT-qPCR, and Western blotting analysis were performed to examine ox-LDL uptake, cell viability, and expression of scavenger receptor-related factors. Inclisiran reduced lipid accumulation in ox-LDL-treated macrophages in a dose-dependent manner. Inclisiran significantly inhibited the levels of total Cholesterol, free Cholesterol, and Cholesterol ester in the supernatant of Raw264.7 cells. Inclisiran reduced ox-LDL uptake and increased Raw264.7 cell viability. Meanwhile, inclisiran downregulated the expression of SR-A, LOX-1, and CD36 and upregulated SR-BI, apoE, and ABCA1. Furthermore, inclisiran increased PPARγ activity and decreased NF-κB activity. An inhibitor of PPARγ (T0070907) reversed the beneficial effects of inclisiran on ox-LDL uptake, NF-κB inactivation, and cytokine expression. In conclusion, these data suggested that inclisiran inhibited the formation of macrophage-derived foam cells by activating the PPARγ pathway.HighlightsInclisiran reduces lipid accumulation in Raw264.7 cells;Inclisiran reduces ox-LDL uptake and increases Raw264.7 cell viability;Inclisiran inhibits foam cell formation by activating the PPARγ pathway.

Keywords

Atherosclerosis; PPARγ; foam cell; inclisiran; lipid accumulation.

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