Targeting PCSK9 to tackle cardiovascular disease

Pharmacology & Therapeutics, Год журнала: 2023, Номер 249, С. 108480 - 108480

Опубликована: Июнь 17, 2023

Lowering blood cholesterol levels efficiently reduces the risk of developing atherosclerotic cardiovascular disease (ASCVD), including coronary artery (CAD), which is main cause death worldwide. CAD caused by plaque formation, comprising deposits in arteries. Proprotein convertase subtilisin kexin/type 9 (PCSK9) was discovered early 2000s and later identified as a key regulator metabolism. PCSK9 induces lysosomal degradation low-density lipoprotein (LDL) receptor liver, responsible for clearing LDL-cholesterol (LDL-C) from circulation. Accordingly, gain-of-function mutations are causative familial hypercholesterolemia, severe condition with extremely high plasma increased ASCVD risk, whereas loss-of-function associated very low LDL-C protection against CAD. Since discovery PCSK9, extensive investigations targeting therapies have been performed. The combined delineation clear biology, genetic variants, crystal structures major drivers antagonistic molecules. Today, two antibody-based inhibitors successfully progressed to clinical application shown be effective reducing mitigating events, myocardial infarction, stroke, death, without any adverse effects. A third siRNA-based inhibitor has FDA-approved but awaits outcome data. In this review, we outline focusing on structure nonsynonymous reported gene elaborate PCSK9-lowering strategies under development. Finally, discuss future perspectives inhibition other disorders beyond disease.

Язык: Английский

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Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 8, 2024

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and revolutionary therapeutic target for hypercholesterolemia its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles wide-ranging implications of PCSK9, extending beyond CVD to emphasize significance diverse physiological pathological states, including liver diseases, infectious autoimmune disorders, notably, cancer. Our exploration offers insights into interaction between PCSK9 low-density lipoprotein receptors (LDLRs), elucidating substantial impact on cholesterol homeostasis health. It also details evolution PCSK9-targeted therapies, translating foundational bench discoveries bedside applications optimized patient care. The advent clinical approval innovative inhibitory therapies (PCSK9-iTs), three monoclonal antibodies (Evolocumab, Alirocumab, Tafolecimab) one small interfering RNA (siRNA, Inclisiran), have marked significant breakthrough medicine. These demonstrated unparalleled efficacy mitigating hypercholesterolemia, reducing risks, showcased profound value applications, offering novel avenues promising future personalized medicine disorders. Furthermore, emerging research, inclusive our findings, unveils PCSK9's potential role indicator cancer prognosis prospective application transformative treatment. highlights aberrant expression various forms, association with prognosis, crucial carcinogenesis immunity. In conclusion, this synthesized integrates existing knowledge providing holistic perspective reshaping paradigms across emphasizes effect PCSK9-iT, underscoring advancing landscape biomedical research capabilities heralding new eras

Язык: Английский

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Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond

Current Atherosclerosis Reports, Год журнала: 2022, Номер 24(10), С. 821 - 830

Опубликована: Июль 29, 2022

Язык: Английский

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Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis

Hepatology, Год журнала: 2023, Номер 78(6), С. 1828 - 1842

Опубликована: Фев. 20, 2023

Background & Aims: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the role of in hepatic metabolism. Approach Results: In treatment hepatocytes with metformin, we found that metformin can transcriptionally activate expression Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. -deficient mice had increased lipid content, triglycerides, cholesterol levels, deficiency suppressed AMPKα phosphorylation led an accumulation nuclear SREBPs, elevated fatty acid biosynthetic activities. Conversely, when overexpressed mouse liver, activated resulted inhibition lipogenesis. Moreover, using diethylnitrosamine-induced HCC model, deletion promoted tumorigenesis development through mammalian target rapamycin cascade. Employing homology modeling virtual screening human metabolome database, demonstrated NAD + endogenous substrate SLC25A47, activity -dependent sirtuin 3 declined mice, followed by inactivation AMPKα. Conclusions: Our findings reveal hepatocyte-specific transporter, one pharmacological targets regulates homeostasis AMPKα, may serve potential drug treating NAFLD HCC.

Язык: Английский

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PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology

Cancers, Год журнала: 2023, Номер 15(5), С. 1397 - 1397

Опубликована: Фев. 22, 2023

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due systemic inflammatory conditions immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is key protein involved in metabolism low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents clinically available involve monoclonal antibodies, SiRNA reduces LDL levels high-risk atherosclerotic cardiovascular disease events multiple patient cohorts. Moreover, induces peripheral tolerance (inhibition cancer cell- recognition), cardiac mitochondrial metabolism, enhances cell survival. The present review summarizes the potential benefits inhibition through selective antibodies siRNA cancer, especially those ICIs therapies, order reduce potentially improve ICIs-related anticancer functions.

Язык: Английский

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Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation

Metabolism, Год журнала: 2024, Номер 152, С. 155774 - 155774

Опубликована: Янв. 6, 2024

Язык: Английский

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VERVE-101, a CRISPR base-editing therapy designed to permanently inactivate hepatic PCSK9 and reduce LDL-cholesterol

Expert Opinion on Investigational Drugs, Год журнала: 2024, Номер 33(8), С. 753 - 756

Опубликована: Июнь 15, 2024

Язык: Английский

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A promising therapy for fatty liver disease: PCSK9 inhibitors

Phytomedicine, Год журнала: 2024, Номер 128, С. 155505 - 155505

Опубликована: Март 6, 2024

Язык: Английский

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The role of PCSK9 in heart failure and other cardiovascular diseases—mechanisms of action beyond its effect on LDL cholesterol

Heart Failure Reviews, Год журнала: 2024, Номер 29(5), С. 917 - 937

Опубликована: Июнь 18, 2024

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading its lysosomal degradation and an increase in (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) production small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs confirmed their high efficacy reducing serum LDLc levels improving prognosis patients atherosclerotic cardiovascular diseases. Most studies focused action of LDLRs subsequent concentrations. Increasing evidence suggests adverse effects PCSK9, particularly vascular wall, may also result from mechanisms independent lipid metabolism. induces expression pro-inflammatory cytokines contributing inflammation within wall promotes apoptosis, pyroptosis, ferroptosis cardiomyocytes thus involved development progression heart failure. The elimination may, therefore, not only be treatment for hypercholesterolaemia but atherosclerosis other system are yet fully understood. This article reviews current understanding contribution Knowledge contribute wider use inhibitors

Язык: Английский

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Insight into the Evolving Role of PCSK9

Metabolites, Год журнала: 2022, Номер 12(3), С. 256 - 256

Опубликована: Март 17, 2022

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of family proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role reduction number low-density lipoprotein receptors (LDLRs) on surface hepatocytes, which leads to an increase level cholesterol blood. mechanism and fact that gain function (GOF) mutations PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) associated with hypocholesterolemia, prompted invention drugs block action. The high efficiency inhibitors (e.g., alirocumab, evolocumab) decreasing cardiovascular risk, pleiotropic effects other lipid-lowering statins) multifunctional character convertases, were cause proceeding studies functions beyond metabolism. In this article, we summarize current knowledge roles different tissues perspectives its clinical use.

Язык: Английский

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