Proprotein convertase subtilisin/kexin type 9: A new target molecule for gene therapy

Banaszewska, Anna; Piechota, Michał; Plewa, Robert

doi:10.2478/s11658-012-0006-7

Cited by 1 publication

(1 citation statement)

References 31 publications

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“…In EC, LPS increases mitochondrial reactive oxygen species (ROS) as well as Lectin-like ox-LDL receptor-1 (LOX-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression [ 8 ], belonging to the proprotein convertase family, regulating low-density lipoprotein (LDL) and cholesterol metabolism [ 9 ]. PCSK9, the attractive molecular target for controlling and decreasing the risk of cardiovascular diseases [ 10 ], is involved in the evolution of atherosclerotic plaques, while the PCSK9 inhibitor (i-PCSK9), evolocumab, displays beneficial effects in vascular function [ 11 ]. To date, the action of PSCK9 in sepsis has not been established [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4

et al. 2023

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Background Endothelial dysfunction and deregulated microRNAs (miRNAs) participate in the development of sepsis and are associated with septic organ failure and death. Here, we explored the role of miR-15b-5p on inflammatory pathways in lipopolysaccharide (LPS)-treated human endothelial cells, HUVEC and TeloHAEC. Methods The miR-15b-5p levels were evaluated in LPS-stimulated HUVEC and TeloHAEC cells by quantitative real-time PCR (qRT–PCR). Functional experiments using cell counting kit-8 (CCK-8), transfection with antagomir, and enzyme-linked immunosorbent assays (ELISA) were conducted, along with investigation of pyroptosis, apoptosis, autophagy, and mitochondrial reactive oxygen species (ROS) by cytofluorometric analysis and verified by fluorescence microscopy. Sirtuin 4 (SIRT4) levels were detected by ELISA and immunoblotting, while proprotein convertase subtilisin-kexin type 9 (PCSK9) expression was determined by flow cytometry (FACS) and immunofluorescence analyses. Dual-luciferase reporter evaluation was performed to confirm the miR-15b-5p–SIRT4 interaction. Results The results showed a correlation among miR-15b-5p, PCSK9, and SIRT4 levels in septic HUVEC and TeloHAEC. Inhibition of miR-15b-5p upregulated SIRT4 content, alleviated sepsis-related inflammatory pathways, attenuated mitochondrial stress, and prevented apoptosis, pyroptosis, and autophagic mechanisms. Finally, a PCSK9 inhibitor (i-PCSK9) was used to analyze the involvement of PCSK9 in septic endothelial injury. i-PCSK9 treatment increased SIRT4 protein levels, opposed the septic inflammatory cascade leading to pyroptosis and autophagy, and strengthened the protective role of miR-15b-5p inhibition. Increased luciferase signal validated the miR-15b-5p–SIRT4 binding. Conclusions Our in vitro findings suggested the miR-15b-5p–SIRT4 axis as a suitable target for LPS-induced inflammatory pathways occurring in sepsis, and provide additional knowledge on the beneficial effect of i-PCSK9 in preventing vascular damage by targeting SIRT4. Graphical Abstract

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