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

Wang, Zhaoping; Chen, Xiangyu; Liu, Jingxing; Wang, Yingcui; Zhang, Suhua

doi:10.1080/08916934.2022.2051142

Cited by 9 publications

(9 citation statements)

References 47 publications

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“…We found that the uptake of oxLDL was raised in macrophages exposed to VSMC PCSK9 -EVs with a concomitant upregulation of CD36, a multifunctional receptor whose expression is significantly increased in macrophages in human carotid atherosclerotic tissue, particularly in advanced stages of atherosclerosis [ 60 ]. On this matter, the silencing of PCSK9 suppresses the ox-LDL-induced up-regulation of proinflammatory cytokine (IL-1α, IL-6, and TNF-α) in THP-1-derived macrophages [ 61 ], whereas Inclisiran, a PCSK9 inhibitor, downregulates the expression of CD36 in macrophages [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells

Greco

Rizzuto

Zara

et al. 2022

IJMS

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Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.

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Section: Discussionmentioning

confidence: 99%

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells

Greco

Rizzuto

Zara

et al. 2022

IJMS

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“…This observation may provide new insights into the cholesterol-lowering mechanism of inclisiran. 258 …”

Section: Cholesterol-related Diseases and Interventionsmentioning

confidence: 99%

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

Duan

Gong

et al. 2022

Sig Transduct Target Ther

133

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Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.

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“…However, chemical modification introduce a disadvantage by compromising the initial chemical and physical characteristics and activities of naturally synthesized, modified, and folded RNA (Morena et al, 2018;Yu et al, 2019;Yu et al, 2020a;Yu et al, 2020b). In fact, recent studies on inclisiran discussed previously suggest possible off-target effects of the therapeutic away from its FDA designated biological activity providing the possibility for off-target effects even in RNAi designed with chemically modifications for target specificity (Christofides et al, 2021;FDA, 2021;Wang et al, 2022).…”

Section: Approaches and Challenges In Delivering Rnai Therapeuticsmentioning

confidence: 99%

“…This suggested that hepatic impairment had little effect on treatment efficacy and showed no issues in the safety or tolerability of inclisiran, which further suggested no need for dose adjustment for patients with mild or moderate hepatic impairment ( Kallend et al, 2022 ). An additional study that was recently published looks into the effects of inclisiran on the formation of oxidized-LDL (ox-LDL)-induced, macrophage-derived foam cells ( Wang et al, 2022 ). In this study, the authors found inclisiran to reduce lipid accumulation and inhibited macrophage-derived foam cell formation through the activation of the peroxisome proliferator-activated receptor gamma (PPAR γ ) pathway ( Wang et al, 2022 ).…”

Section: Therapeutic Sirnasmentioning

confidence: 99%

“…An additional study that was recently published looks into the effects of inclisiran on the formation of oxidized-LDL (ox-LDL)-induced, macrophage-derived foam cells ( Wang et al, 2022 ). In this study, the authors found inclisiran to reduce lipid accumulation and inhibited macrophage-derived foam cell formation through the activation of the peroxisome proliferator-activated receptor gamma (PPAR γ ) pathway ( Wang et al, 2022 ). Since activation of the PPAR γ pathway is important in fatty acid uptake and lipogenesis, the results of this study suggest a possible off-target effect of inclisiran by increasing the expression of increased both the gene and protein expression of PPAR γ ( Christofides et al, 2021 ; Wang et al, 2022 ).…”

Section: Therapeutic Sirnasmentioning

confidence: 99%

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RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies

Traber

2022

J Pharmacol Exp Ther

102

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RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biologic activity away from their natural equivalents. Novel technologies in development today seek to use intact cells to yield true biologic RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiologic and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA-approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran) as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biologic RNAi agents for research and development. SIGNIFICANCE STATEMENT In our review, we summarize the major concepts of RNA interference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of US Food and Drug Administration-approved RNAi medications and those siRNAs and miRNA-based therapeutics that entered the clinical investigations. Novel approaches to producing new true biological RNAi molecules for research and development are highlighted.

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

Cited by 9 publications

References 47 publications

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies

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