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The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Lipid Metabolism".

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 21457

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Prof. Dr. Marianne Abifadel

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Guest Editor

1. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint Joseph University of Beirut, Beirut 1004 2020, Lebanon
2. Laboratory for Vascular Translational Science, Centre Hospitalo-Universitaire Xavier Bichat, APHP, INSERM U1148, Université de Paris, 75018 Paris, France
Interests: pcsk9; cholesterol metabolism; cardiovascular disease; genetics; genomics; familial hypercholesterolemia; thoracic aortic aneurysm; molecular diagnosis; communicable and noncommunicable diseases; pathogens

Prof. Dr. Catherine Boileau

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Guest Editor

1. Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, 46 rue Henri 17 Huchard, 75018 Paris, France
2. Laboratory for Vascular Translational Science, Centre Hospitalo-Universitaire Xavier Bichat, APHP, INSERM U1148, Université de Paris, 75018 Paris, France
Interests: cardiovascular disease; genetics; genomics; FH; cholesterol metabolism; atheroma; thoracic aortic aneurysm; molecular diagnosis

Dr. Nabil G. Seidah

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Guest Editor

Montreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, 110 Pine Ave West, Montreal, QC H2W1R7, Canada
Interests: proprotein convertases; precursor processing; enzymology; cardiovascular and metabolic diseases; cancer/metastasis; viral and pathogen infections; molecular and cell biology; neuroendocrinology

Special Issue Information

Dear Colleagues,

Since our first identification in 2003 of PCSK9 and its natural mutations causing familial hypercholesterolemia and its relationship to cardiovascular complications, a huge field of research on PCSK9 has emerged leading to clinical prescriptions of a new class of lipid lowering drugs. Anti-PCSK9 antibodies are now very efficient in fighting hypercholesterolemia and cardiovascular diseases. The PCSK9 story is an amazing example of successful translational research that revolutionized the field of LDL-cholesterol. However, many aspects of the PCSK9 biology still need to be elucidated, which may lead to new and exciting applications.

This Special Issue of Metabolites, “The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications, and Beyond” will be dedicated to PCSK9 and to anti-PCSK9 therapies, notably antibodies and siRNA, in cholesterol and cardiovascular diseases.

This issue will include PCSK9 hepatic but also extrahepatic functions and their implications in atherosclerosis through LDL-cholesterol homeostasis or beyond. Additionally, it will cover the role of PCSK9 in cancer, inflammation, infectious, and neurological diseases. It will provide new insights into genetics, molecular, biochemical, cellular, animal, pharmacological, and clinical studies from fundamental and applied research angles, as well as the various roles of PCSK9, the measurement of its various forms, and its modulation by nutritional or therapeutic approaches.

Dr. Marianne Abifadel
Prof. Dr. Catherine Boileau
Dr. Nabil G. Seidah
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

PCSK9
cholesterol
anti-PCSK9
cardiovascular diseases
genetic
atherosclerosis
alirocumab
evolocumab
inclisiran

Published Papers (7 papers)

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Research

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11 pages, 298 KiB

Open AccessArticle

Lipid Parameters and Proprotein Convertase Subtilisin/Kexin Type 9 in Healthy Lebanese Adults

by Marie-Hélène Gannagé-Yared, Elie Naous, Anis Al Achkar, Wadih Issa, Ghassan Sleilaty, Vanda Barakett-Hamade and Marianne Abifadel

Metabolites 2022, 12(8), 690; https://doi.org/10.3390/metabo12080690 - 26 Jul 2022

Viewed by 1184

Abstract

Background: High levels of non-HDL cholesterol (non-HDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), and Proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as low levels of HDL-C are strongly associated with cardiovascular disease (CVD). Our study aims to estimate the prevalence of dyslipidemia and high Lp(a) in the Lebanese population and to study the relationship of these variables with gender, age, body mass index (BMI), and PCSK9. Methods: This cross-sectional study was carried out on a sample of healthy volunteers aged 18 to 65. Blood samples were drawn from volunteers for total cholesterol (TC), HDL-C, TG, PCSK9, and Lp(a) measurements. Non-HDL-C was calculated by subtracting HDL-C from TC. Results: In total, 303 volunteer subjects with an average age of 38.9 years were included in the study. Respectively, 44%, 29.8%, and 44% of men had high non-HDL-C and TG with low HDL-C versus 23.5%, 8%, and 37% in women. Non-HDL-C and TG were significantly higher in men than in women, while the reverse was observed for HDL-C (p < 0.0001 for the three comparisons). Non-HDL-C and TG were significantly correlated with age and BMI (p< 0.0001 for all correlations), while HDL-C was inversely correlated with BMI (p < 0.0001) but not with age. Abnormal Lp(a) levels (≥75 nmol/L) were found in 19.1% of the population, predominantly in women (24.1% versus 13.4% in men, p = 0.004). The median PCSK9 and its interquartile was 300 (254–382) ng/L with no gender difference (p = 0.18). None of the following factors: gender, age, BMI, non-HDL-C, HDL-C, or TG, were independently associated with Lp(a), while PCSK9 was significantly correlated with age, non-HDL-C, and TG in both men and women and inversely correlated with HDL-C in men. Dyslipidemia is very common in the Lebanese population and is associated with age, high BMI, and male sex. Lp(a) is higher in women without any correlation with the lipid profile, whereas PCSK9 is associated with non-HDL-C and TG. Further studies are needed to evaluate the potential role of Lp(a) and PCSK9 in predicting CVD in healthy populations. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

13 pages, 779 KiB

Open AccessArticle

Circulating PCSK9 Linked to Dyslipidemia in Lebanese Schoolchildren

by Yara Azar, Marie-Hélène Gannagé-Yared, Elie Naous, Carine Ayoub, Yara Abou Khalil, Elise Chahine, Sandy Elbitar, Youmna Ghaleb, Catherine Boileau, Mathilde Varret, Petra El Khoury and Marianne Abifadel

Metabolites 2022, 12(6), 504; https://doi.org/10.3390/metabo12060504 - 31 May 2022

Cited by 1 | Viewed by 1577

Abstract

In adults, elevated levels of circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) have been associated with increased Low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and worse cardiovascular outcomes. However, few studies analyzed the relation between PCSK9 and lipid parameters in pediatric populations. The aim of our study is to evaluate the distribution and the correlation of serum PCSK9 levels with lipid parameters in a sample of Lebanese school children. Using an immunofluorescence assay, we measured serum PCSK9 levels in 681 school children recruited from ten public and private Lebanese schools. We analyzed the association between PCSK9 and age, sex, Body Mass Index (BMI), and lipid parameters (total cholesterol (TC), LDL-C, TG, High-density lipoprotein cholesterol (HDL-C), non-HDL-C, and lipoprotein (a) (Lp(a)). Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C (p value < 0.0001) but not with TG, HDL-C, and Lp(a). PCSK9 levels were also significantly higher in children with high TC, LDL-C, and non-HDL-C (p values = 0.0012, 0.0002, 0.001, respectively). No significant gender differences in PCSK9 were found. In addition, no significant associations between PCSK9 and both age and BMI percentiles were observed. In girls, no difference in PCSK9 values was observed according to menarche while in boys, testosterone levels were not significantly associated with PCSK9. Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C levels. Further studies are needed to find if PCSK9 measurements have an additional value to predict future cardiovascular outcomes in pediatric populations. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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9 pages, 1923 KiB

Open AccessArticle

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

by Laura Canclini, Amir Mohammad Malvandi, Patrizia Uboldi, Najoua Jabnati, Liliana Grigore, Alberto Zambon, Andrea Baragetti and Alberico Luigi Catapano

Metabolites 2021, 11(12), 861; https://doi.org/10.3390/metabo11120861 - 10 Dec 2021

Viewed by 2386

Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is key regulator of low-density lipoprotein (LDL) metabolism. A significant proportion of PCSK9 is believed to be associated with LDL in plasma as it circulates, although this finding is still a matter of debate. The purpose of this study was to establish an experimental method to investigate the presence of such an interaction in the bloodstream. We compared a number of well-established methods for lipoprotein (LP) isolation to clarify whether PCSK9 associates differently to circulating lipoproteins, such as KBr gradient ultracentrifugation, physical precipitation of ApoB-LPs, fast protein liquid chromatography (FPLC) and iodixanol gradient ultracentrifugation. Our data show heterogeneity in PCSK9 association to lipoproteins according to the method used. Two methods, iodixanol ultracentrifugation and column chromatography, which did not involve precipitation or high salt concentration, consistently showed an interaction of PCSK9 with a subfraction of LDL that appeared to be more buoyant and have a lower size than average LDL. The percent of PCSK9 association ranged from 2 to 30% and did not appear to correlate to plasma or LDL cholesterol levels. The association of PCSK9 to LDL appeared to be sensitive to high salt concentrations. FPLC and iodixanol gradient ultracentrifugation appeared to be the most suitable methods for the study of this association. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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Review

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25 pages, 1480 KiB

Open AccessReview

Insight into the Evolving Role of PCSK9

by Mateusz Maligłówka, Michał Kosowski, Marcin Hachuła, Marcin Cyrnek, Łukasz Bułdak, Marcin Basiak, Aleksandra Bołdys, Grzegorz Machnik, Rafał Jakub Bułdak and Bogusław Okopień

Metabolites 2022, 12(3), 256; https://doi.org/10.3390/metabo12030256 - 17 Mar 2022

Cited by 22 | Viewed by 4525

Abstract

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

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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12 pages, 643 KiB

Open AccessReview

Pleiotropic Effects of PCSK9: Focus on Thrombosis and Haemostasis

by Marianna Puccini, Ulf Landmesser and Ursula Rauch

Metabolites 2022, 12(3), 226; https://doi.org/10.3390/metabo12030226 - 04 Mar 2022

Cited by 12 | Viewed by 3072

Abstract

The proprotein convertase subtilisin/keying 9 (PCSK9) is a serine protease that has gained importance in recent years as a drug target, mainly due to its effect on cholesterol metabolism in promoting the degradation of the low-density lipoprotein receptor (LDLR). However, this protease may also play an important role in lipid-independent reactions, including the process of thrombogenesis. Considering this, we reviewed the effects and implications of PCSK9 on platelet function and blood coagulation. PCSK9 knockout mice exhibited reduced platelet activity and developed less agonist-induced arterial thrombi compared to the respective control animals. This is in line with known research that elevated blood levels of PCSK9 are associated with an increased platelet reactivity and total number of circulating platelets in humans. Moreover, PCSK9 also has an effect on crucial factors of the coagulation cascade, such as increasing factor VIII plasma levels, since the degradation of this blood clotting factor is promoted by the LDLR. The aforementioned pleiotropic effects of the PCSK9 are important to take into account when evaluating the clinical benefit of PCSK9 inhibitors. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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15 pages, 1275 KiB

Open AccessReview

The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases

by Paul F. Lebeau, Khrystyna Platko, Jae Hyun Byun, Yumna Makda and Richard C. Austin

Metabolites 2022, 12(3), 215; https://doi.org/10.3390/metabo12030215 - 26 Feb 2022

Cited by 9 | Viewed by 3546

Abstract

The importance of the proprotein convertase subtilisin/kexin type-9 (PCSK9) gene was quickly recognized by the scientific community as the third locus for familial hypercholesterolemia. By promoting the degradation of the low-density lipoprotein receptor (LDLR), secreted PCSK9 protein plays a vital role in the regulation of circulating cholesterol levels and cardiovascular disease risk. For this reason, the majority of published works have focused on the secreted form of PCSK9 since its initial characterization in 2003. In recent years, however, PCSK9 has been shown to play roles in a variety of cellular pathways and disease contexts in LDLR-dependent and -independent manners. This article examines the current body of literature that uncovers the intracellular and LDLR-independent roles of PCSK9 and also explores the many downstream implications in metabolic diseases. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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13 pages, 907 KiB

Open AccessReview

Gene Therapy Targeting PCSK9

by Julius L. Katzmann, Arjen J. Cupido and Ulrich Laufs

Metabolites 2022, 12(1), 70; https://doi.org/10.3390/metabo12010070 - 12 Jan 2022

Cited by 18 | Viewed by 3747

Abstract

The last decades of research in cardiovascular prevention have been characterized by successful bench-to-bedside developments for the treatment of low-density lipoprotein (LDL) hypercholesterolemia. Recent examples include the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies, small interfering RNA and antisense RNA drugs. The cumulative effects of LDL cholesterol on atherosclerosis make early, potent, and long-term reductions in LDL cholesterol desirable—ideally without the need of regular intake or application of medication and importantly, without side effects. Current reports show durable LDL cholesterol reductions in primates following one single treatment with PCSK9 gene or base editors. Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes. Provided safety and documentation of a reduction in cardiovascular events, this novel technique has the potential to fundamentally change our current concepts of cardiovascular prevention. In this review, the application of the CRISPR/Cas system is explained and the current state of in vivo approaches of PCSK9 editing is presented. Full article

(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)

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The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond

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