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Ma H, Ma W, Liu Y, Chen L, Ding P. Effects of Alirocumab and Evolocumab on Cardiovascular Mortality and LDL-C: Stratified According to the Baseline LDL-C Levels. Rev Cardiovasc Med 2025; 26:26980. [PMID: 40351695 PMCID: PMC12059789 DOI: 10.31083/rcm26980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 05/14/2025] Open
Abstract
Background A meta-analysis was conducted to determine whether the cardiovascular mortality and lipid-lowering effects of alirocumab and evolocumab are influenced by various baseline low-density lipoprotein cholesterol (LDL-C) levels. Methods We searched for literature published before June 2023. Eligible randomized controlled trials (RCTs) included adults treated with alirocumab or evolocumab and reported LDL-C changes and cardiovascular deaths. The primary endpoints were cardiovascular mortality and percent changes in LDL-C from baseline. Results Forty-one RCTs were included in the meta-analysis. Evolocumab did not significantly affect the outcome of cardiovascular mortality whether the baseline data were greater than 100 mg/dL or less than 100 mg/dL. However, the stratified result showed that alirocumab decreased the risk of cardiovascular mortality in patients with a baseline LDL-C level of ≥100 mg/dL (relative risk (RR) 0.45; 95% CI: 0.22 to 0.92; p = 0.03). In terms of lipid-lowering efficacy, alirocumab (mean difference (MD) -56.62%; 95% CI: -60.70% to -52.54%; p < 0.001) and evolocumab (MD -68.10%; 95% CI: -74.85% to -61.36%; p < 0.001) yielded the highest percentage reduction in LDL-C level when baseline levels were 70-100 mg/dL, while the smallest reduction in alirocumab (MD -37.26%; 95% CI: -44.06% to -30.46%; p < 0.001) and evolocumab (MD -37.55%; 95% CI: -40.47% to -34.63%; p < 0.001) occurred with baseline LDL-C levels of ≥160 mg/dL. Conclusions Alirocumab and evolocumab presented a better lipid-lowering effect when the baseline LDL-C levels were <100 mg/dL. Alirocumab was associated with a significant reduction in cardiovascular mortality at baseline LDL-C levels of ≥100 mg/dL. This finding can have significant implications for the development of personalized drug therapy. The PROSPERO Registration CRD42023446723, https://www.crd.york.ac.uk/PROSPERO/view/CRD42023446723.
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Affiliation(s)
- Hui Ma
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Wenfang Ma
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Yang Liu
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Lixing Chen
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Peng Ding
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
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Shekarchizadeh Esfahani M, Siavash M, Sajad RS, Ramezani Ahmadi A, Karimifar M, Akbari M, Shekarchizadeh M. Immunotherapy and vaccine-based approaches for atherosclerosis prevention: a systematic review study. BMC Cardiovasc Disord 2025; 25:201. [PMID: 40114074 PMCID: PMC11924661 DOI: 10.1186/s12872-025-04634-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/06/2025] [Indexed: 03/22/2025] Open
Abstract
INTRODUCTION Cardiovascular disease is a major global health issue, and atherosclerosis is a leading cause of cardiovascular conditions. Traditional approaches for managing atherosclerosis have limitations, creating a need for alternative preventive strategies such as vaccines. METHODS The authors conducted a systematic review following Cochrane Handbook and PRISMA guidelines. They searched multiple databases for studies on preventive vaccines against atherosclerosis, including clinical trials and experimental models. The search period was from 1950 to August 2024. RESULTS After screening and evaluation, 47 studies were included in the systematic review. The studies investigated various vaccine candidates and immunization strategies. Vaccination goals involve targeting proteins that are found in higher quantities in individuals with atherosclerosis, such as oxidized low-density lipoprotein (LDL), apolipoprotein B-100, proprotein convertase subtilisin/kexin type-9 serine protease (PCSK9), cholesteryl ester transfer protein (CETP), and heat shock proteins HSP60 and HSP65. The review highlights the potential of vaccines in preventing atherosclerosis by targeting specific antigens, modulating lipoprotein metabolism, and enhancing immune responses. Promising approaches included PCSK9 inhibitors, virus-like particle (VLP)-based vaccines, and gene-editing techniques. Monoclonal antibodies like alirocumab, designed to inhibit PCSK9, were also effective in reducing LDL cholesterol levels. CONCLUSION This systematic review provides insights into the progress, challenges, and future directions of preventive vaccine research against atherosclerosis. The findings support the development of effective vaccines to complement existing preventive strategies and reduce the global burden of cardiovascular diseases. CLINICAL TRIAL NUMBER It is not applicable.
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Affiliation(s)
| | - Mansour Siavash
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Raheleh Sadat Sajad
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Mozhgan Karimifar
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojtaba Akbari
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masood Shekarchizadeh
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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Pei J, Kinch LN, Cong Q. Computational analysis of propeptide-containing proteins and prediction of their post-cleavage conformation changes. Proteins 2024; 92:1206-1219. [PMID: 38775337 DOI: 10.1002/prot.26702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/10/2024] [Accepted: 04/29/2024] [Indexed: 10/26/2024]
Abstract
A propeptide is removed from a precursor protein to generate its active or mature form. Propeptides play essential roles in protein folding, transportation, and activation and are present in about 2.3% of reviewed proteins in the UniProt database. They are often found in secreted or membrane-bound proteins including proteolytic enzymes, hormones, and toxins. We identified a variety of globular and nonglobular Pfam domains in protein sequences designated as propeptides, some of which form intramolecular interactions with other domains in the mature proteins. Propeptide-containing enzymes mostly function as proteases, as they are depleted in other enzyme classes such as hydrolases acting on DNA and RNA, isomerases, and lyases. We applied AlphaFold to generate structural models for over 7000 proteins with propeptides having no less than 20 residues. Analysis of residue contacts in these models revealed conformational changes for over 300 proteins before and after the cleavage of the propeptide. Examples of conformation change occur in several classes of proteolytic enzymes in the families of subtilisins, trypsins, aspartyl proteases, and thermolysin-like metalloproteases. In most of the observed cases, cleavage of the propeptide releases the constraints imposed by the covalent bond between the propeptide and the mature protein, and cleavage enables stronger interactions between the propeptide and the mature protein. These findings suggest that post-cleavage propeptides could play critical roles in regulating the activity of mature proteins.
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Affiliation(s)
- Jimin Pei
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lisa N Kinch
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Qian Cong
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Chen C, Wei FF, Dong Y, Liu C. Early Management of Blood Lipid Levels with Non-Statin Lipid-Lowering Drugs in Acute Coronary Syndrome: A Mini Review. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07587-9. [PMID: 38951453 DOI: 10.1007/s10557-024-07587-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2024] [Indexed: 07/03/2024]
Abstract
Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality, despite many improvements in its prevention and management. Lipid management is an important aspect of secondary prevention after ACS. Previous studies indicate that the early use of intensive statin therapy in patients with ACS may alleviate the risk of recurrent cardiovascular events and mortality. However, many patients do not reach the target low-density lipoprotein cholesterol (LDL-C) level of < 55 mg/dL with statin monotherapy, and muscle-related adverse effects caused by statins hinder adherence to treatment. Novel non-statin agents are recommended for patients who cannot achieve the target LDL-C levels with high-intensity statin therapy and those with statin intolerance. The combination of statins and non-statins may synergistically affect intensively lowering LDL-C through different mechanisms, which could lead to better cardiovascular outcomes than statin monotherapy. However, it remains uncertain whether the early use of combination lipid-lowering therapy is more beneficial. The present review summarizes the benefits of intensive statin monotherapy and their early combination with non-statin medications including ezetimibe, PCSK9 inhibitors, inclisiran, and bempedoic acid (BDA) in the management of ACS.
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Affiliation(s)
- Chen Chen
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, PR China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, PR China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, PR China
| | - Fang-Fei Wei
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, PR China.
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, PR China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, PR China.
| | - Yugang Dong
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, PR China.
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, PR China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, PR China.
| | - Chen Liu
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, PR China.
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, PR China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, PR China.
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Muzammil K, Hooshiar MH, Varmazyar S, Omar TM, Karim MM, Aadi S, Kalavi S, Yasamineh S. Potential use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and prevention method in viral infection. Microb Cell Fact 2024; 23:90. [PMID: 38528584 PMCID: PMC10962113 DOI: 10.1186/s12934-024-02355-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/03/2024] [Indexed: 03/27/2024] Open
Abstract
Cellular lipid membranes serve as the primary barrier preventing viral infection of the host cell and provide viruses with a critical initial point of contact. Occasionally, viruses can utilize lipids as viral receptors. Viruses depend significantly on lipid rafts for infection at virtually every stage of their life cycle. The pivotal role that proprotein convertase subtilisin/kexin Type 9 (PCSK9) plays in cholesterol homeostasis and atherosclerosis, primarily by post-transcriptionally regulating hepatic low-density lipoprotein receptor (LDLR) and promoting its lysosomal degradation, has garnered increasing interest. Conversely, using therapeutic, fully humanized antibodies to block PCSK9 leads to a significant reduction in high LDL cholesterol (LDL-C) levels. The Food and Drug Administration (FDA) has approved PCSK9 inhibitors, including inclisiran (Leqvio®), alirocumab (Praluent), and evolocumab (Repatha). At present, active immunization strategies targeting PCSK9 present a compelling substitute for passive immunization through the administration of antibodies. In addition to the current inquiry into the potential therapeutic application of PCSK9 inhibition in human immunodeficiency virus (HIV)-infected patients for hyperlipidemia associated with HIV and antiretroviral therapy (ART), preclinical research suggests that PCSK9 may also play a role in inhibiting hepatitis C virus (HCV) replication. Furthermore, PCSK9 inhibition has been suggested to protect against dengue virus (DENV) potentially and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses. Recent evidence regarding the impact of PCSK9 on a variety of viral infections, including HCV, HIV, DENV, and SARS-CoV-2, is examined in this article. As a result, PCSK9 inhibitors and vaccines may serve as viable host therapies for viral infections, as our research indicates that PCSK9 is significantly involved in the pathogenesis of viral infections.
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Affiliation(s)
- Khursheed Muzammil
- Department of Public Health, College of Applied Medical Sciences, King Khalid University, Khamis Mushait Campus, Abha, KSA, Saudi Arabia
| | | | - Shirin Varmazyar
- Department of Medicine, Shahroud Islamic azad university of medical sciences, Sharoud, Iran
| | - Thabit Moath Omar
- Department of Medical Laboratory Technics, Al-Noor University College, Nineveh, Iraq
| | - Manal Morad Karim
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | - Sadeq Aadi
- College of Dentistry, Al-Mustaqbal University, Babylon, 51001, Iraq
| | - Shaylan Kalavi
- Department of Clinical Pharmacy, faculty of pharmacy, Islamic Azad University of Medical Sciences, Tehran, Iran.
| | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
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Alavi O, Hozhabri M, Sheikhesmaili F, Moradzad M, Rahbari R, Moradi N, Vahabzadeh Z. PCSK9 polymorphism rs505151 is associated with the risk of NAFLD in Iranian participants: A case-control study. GENE REPORTS 2024; 34:101864. [DOI: 10.1016/j.genrep.2023.101864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
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7
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Macvanin MT, Gluvic ZM, Klisic AN, Manojlovic MS, Suri JS, Rizzo M, Isenovic ER. The Link between miRNAs and PCKS9 in Atherosclerosis. Curr Med Chem 2024; 31:6926-6956. [PMID: 37990898 DOI: 10.2174/0109298673262124231102042914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 11/23/2023]
Abstract
Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, and miRNA levels manipulation by therapeutic agents.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran M Gluvic
- Department of Endocrinology and Diabetes, School of Medicine, University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra N Klisic
- Faculty of Medicine, Center for Laboratory Diagnostic, Primary Health Care Center, University of Montenegro, Podgorica, Montenegro
| | - Mia S Manojlovic
- Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Novi Sad, Serbia
| | - Jasjit S Suri
- Stroke Monitoring and Diagnostic Division, Athero- Point™, Roseville, CA95661, USA
| | - Manfredi Rizzo
- Department of Health Promotion, School of Medicine, Mother and Child Care and Medical Specialties (Promise), University of Palermo, Palermo, Italy
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Larrea-Sebal A, Jebari-Benslaiman S, Galicia-Garcia U, Jose-Urteaga AS, Uribe KB, Benito-Vicente A, Martín C. Predictive Modeling and Structure Analysis of Genetic Variants in Familial Hypercholesterolemia: Implications for Diagnosis and Protein Interaction Studies. Curr Atheroscler Rep 2023; 25:839-859. [PMID: 37847331 PMCID: PMC10618353 DOI: 10.1007/s11883-023-01154-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2023] [Indexed: 10/18/2023]
Abstract
PURPOSE OF REVIEW Familial hypercholesterolemia (FH) is a hereditary condition characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), which increases the risk of cardiovascular disease if left untreated. This review aims to discuss the role of bioinformatics tools in evaluating the pathogenicity of missense variants associated with FH. Specifically, it highlights the use of predictive models based on protein sequence, structure, evolutionary conservation, and other relevant features in identifying genetic variants within LDLR, APOB, and PCSK9 genes that contribute to FH. RECENT FINDINGS In recent years, various bioinformatics tools have emerged as valuable resources for analyzing missense variants in FH-related genes. Tools such as REVEL, Varity, and CADD use diverse computational approaches to predict the impact of genetic variants on protein function. These tools consider factors such as sequence conservation, structural alterations, and receptor binding to aid in interpreting the pathogenicity of identified missense variants. While these predictive models offer valuable insights, the accuracy of predictions can vary, especially for proteins with unique characteristics that might not be well represented in the databases used for training. This review emphasizes the significance of utilizing bioinformatics tools for assessing the pathogenicity of FH-associated missense variants. Despite their contributions, a definitive diagnosis of a genetic variant necessitates functional validation through in vitro characterization or cascade screening. This step ensures the precise identification of FH-related variants, leading to more accurate diagnoses. Integrating genetic data with reliable bioinformatics predictions and functional validation can enhance our understanding of the genetic basis of FH, enabling improved diagnosis, risk stratification, and personalized treatment for affected individuals. The comprehensive approach outlined in this review promises to advance the management of this inherited disorder, potentially leading to better health outcomes for those affected by FH.
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Affiliation(s)
- Asier Larrea-Sebal
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940, Leioa, Spain
- Fundación Biofisika Bizkaia, 48940, Leioa, Spain
| | - Shifa Jebari-Benslaiman
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940, Leioa, Spain
| | - Unai Galicia-Garcia
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940, Leioa, Spain
| | - Ane San Jose-Urteaga
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
| | - Kepa B Uribe
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
| | - Asier Benito-Vicente
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940, Leioa, Spain
| | - César Martín
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48080, Bilbao, Spain.
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940, Leioa, Spain.
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Zhang Y, Chen H, Hong L, Wang H, Li B, Zhang M, Li J, Yang L, Liu F. Inclisiran: a new generation of lipid-lowering siRNA therapeutic. Front Pharmacol 2023; 14:1260921. [PMID: 37900173 PMCID: PMC10611522 DOI: 10.3389/fphar.2023.1260921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/03/2023] [Indexed: 10/31/2023] Open
Abstract
Atherosclerotic heart disease (AHD) is a major cause of morbidity and mortality worldwide. Lowering low-density lipoprotein cholesterol (LDL-C) levels is a key strategy to prevent and treat AHD. Inclisiran is a novel siRNA drug that targets proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression and reduces LDL-C levels with only two or three injections per year. This review summarizes the mechanism, efficacy, safety, and applications of Inclisiran in various populations and settings, based on recent literature. It also compares Inclisiran with other lipid-lowering drugs, especially other PCSK9 inhibitors. We conclude that Inclisiran is a promising lipid-lowering agent that can provide convenience and effectiveness for patients with high cardiovascular risk. However, some challenges and limitations remain for Inclisiran, such as its long-term safety and efficacy, its cost-effectiveness and accessibility, and its interactions and synergies with other drugs. These issues need further investigation and evaluation in future studies.
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Affiliation(s)
- Yanzhen Zhang
- Department of Rheumatology, Shunyi Hospital, Beijing Traditional Chinese Medicine Hospital, Beijing, China
| | - Huaigang Chen
- Medical College of Nanchang University, Nanchang, China
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Lang Hong
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Hong Wang
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Bin Li
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Mengyin Zhang
- Pharmacy Department, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Jiamei Li
- Laboratory Department, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Liu Yang
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Fan Liu
- Department of Hematology Jiangxi Hospital of Traditional Chinese Medicine, Nanchang, China
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Lucà F, Oliva F, Rao CM, Abrignani MG, Amico AF, Di Fusco SA, Caretta G, Di Matteo I, Di Nora C, Pilleri A, Ceravolo R, Rossini R, Riccio C, Grimaldi M, Colivicchi F, Gulizia MM. Appropriateness of Dyslipidemia Management Strategies in Post-Acute Coronary Syndrome: A 2023 Update. Metabolites 2023; 13:916. [PMID: 37623860 PMCID: PMC10456563 DOI: 10.3390/metabo13080916] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
It has been consistently demonstrated that circulating lipids and particularly low-density lipoprotein cholesterol (LDL-C) play a significant role in the development of coronary artery disease (CAD). Several trials have been focused on the reduction of LDL-C values in order to interfere with atherothrombotic progression. Importantly, for patients who experience acute coronary syndrome (ACS), there is a 20% likelihood of cardiovascular (CV) event recurrence within the two years following the index event. Moreover, the mortality within five years remains considerable, ranging between 19 and 22%. According to the latest guidelines, one of the main goals to achieve in ACS is an early improvement of the lipid profile. The evidence-based lipid pharmacological strategy after ACS has recently been enhanced. Although novel lipid-lowering drugs have different targets, the result is always the overexpression of LDL receptors (LDL-R), increased uptake of LDL-C, and lower LDL-C plasmatic levels. Statins, ezetimibe, and PCSK9 inhibitors have been shown to be safe and effective in the post-ACS setting, providing a consistent decrease in ischemic event recurrence. However, these drugs remain largely underprescribed, and the consistent discrepancy between real-world data and guideline recommendations in terms of achieved LDL-C levels represents a leading issue in secondary prevention. Although the cost-effectiveness of these new therapeutic advancements has been clearly demonstrated, many concerns about the cost of some newer agents continue to limit their use, affecting the outcome of patients who experienced ACS. In spite of the fact that according to the current recommendations, a stepwise lipid-lowering approach should be adopted, several more recent data suggest a "strike early and strike strong" strategy, based on the immediate use of statins and, eventually, a dual lipid-lowering therapy, reducing as much as possible the changes in lipid-lowering drugs after ACS. This review aims to discuss the possible lipid-lowering strategies in post-ACS and to identify those patients who might benefit most from more powerful treatments and up-to-date management.
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Affiliation(s)
- Fabiana Lucà
- Cardiology Department, Grande Ospedale Metropolitano, AO Bianchi Melacrino Morelli, 89129 Reggio Calabria, Italy;
| | - Fabrizio Oliva
- De Gasperis Cardio Center, Niguarda Hospital, 20162 Milan, Italy
| | - Carmelo Massimiliano Rao
- Cardiology Department, Grande Ospedale Metropolitano, AO Bianchi Melacrino Morelli, 89129 Reggio Calabria, Italy;
| | | | | | - Stefania Angela Di Fusco
- Clinical and Rehabilitation Cardiology Department, San Filippo Neri Hospital, ASL Roma 1, 00100 Roma, Italy
| | - Giorgio Caretta
- Sant’Andrea Hospital, ASL 5 Regione Liguria, 19124 La Spezia, Italy
| | - Irene Di Matteo
- De Gasperis Cardio Center, Niguarda Hospital, 20162 Milan, Italy
| | - Concetta Di Nora
- Department of Cardiothoracic Science, Azienda Sanitaria Universitaria Integrata di Udine, 33100 Udine, Italy
| | - Anna Pilleri
- Cardiology Unit, Brotzu Hospital, 09121 Cagliari, Italy
| | - Roberto Ceravolo
- Cardiology Department, Giovanni Paolo II Hospital, 88046 Lamezia Terme, Italy
| | - Roberta Rossini
- Cardiology Unit, Ospedale Santa Croce e Carle, 12100 Cuneo, Italy
| | - Carmine Riccio
- Cardiovascular Department, Sant’Anna e San Sebastiano Hospital, 81100 Caserta, Italy
| | - Massimo Grimaldi
- Department of Cardiology, General Regional Hospital “F. Miulli”, 70021 Bari, Italy
| | - Furio Colivicchi
- Clinical and Rehabilitation Cardiology Department, San Filippo Neri Hospital, ASL Roma 1, 00100 Roma, Italy
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11
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Zhu D, Qin H, Wang X, Jia Y, Wang X, Zhang L. Discovery of [5,5'-bibenzo[d][1,3]dioxol]-6-substituted amine derivatives as potent proprotein convertase subtilisin/kexin type 9 inhibitors. Chem Biol Drug Des 2023; 102:153-167. [PMID: 37170061 DOI: 10.1111/cbdd.14264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/20/2023] [Accepted: 05/01/2023] [Indexed: 05/13/2023]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hyperlipidemia. In discovery of novel small molecules that interfere PCSK9/LDLR protein-protein interaction (PPI), structural modification was performed based on our previously derived compounds. A series of [5,5'-bibenzo[d][1,3]dioxol]-6-amine analogs were designed and synthesized for the activity evaluation. In the PCSK9/LDLR PPI impairing test, molecules D28 and D29, exhibited remarkable inhibitory potency with IC50 values of 8.30 and 6.70 μM compared with SBC-115337 (17.89 μM), respectively. Molecular docking predicted the binding pattern of compounds D28 and D29 in the LDLR binding site of PCSK9. Hydrophobic interactions play an important role in the binding of aromatic molecular fragments to the pockets in the PCSK9/LDLR binding interface. Further LDLR expression and LDL uptake studies revealed that both D28 and D29 restored LDLR expression on the surface of hepatic HepG2 cells and improved extracellular LDL uptake in the presence of PCSK9. It is significant that molecules D28 and D29 exhibited potential for the treatment of hyperlipidemia in current in vitro investigations. Generally, lead compounds with novel structures were developed in the present study for further design of lipid-lowering molecules by targeting PCSK9/LDLR PPI.
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Affiliation(s)
- Dongqi Zhu
- Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hongyu Qin
- Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xiaojing Wang
- Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yuping Jia
- Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Xuejian Wang
- Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, China
| | - Lei Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China
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12
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Ouyang M, Li C, Hu D, Peng D, Yu B. Mechanisms of unusual response to lipid-lowering therapy: PCSK9 inhibition. Clin Chim Acta 2023; 538:113-123. [PMID: 36403664 DOI: 10.1016/j.cca.2022.11.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/13/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022]
Abstract
The efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has broadened lipid-lowering therapy thus providing decreased risk in atherosclerotic cardiovascular disease. Unfortunately, the widespread use of PCSK9 inhibitors (PCSK9i), ie, monoclonal antibodies, has led to the findings of unusual responsiveness, ie, a phenomenon defined as an LDL-C reduction of <30% vs the average LDL-C reduction efficacy of 50-60%. This unusual responsiveness to PCSK9i is attributable to several factors, ie, lack of adherence, impaired absorption, poor distribution or early elimination as well as abnormal effects of PCSK9i in the presence of anti-antibodies or mutations in PCSK9 and LDLR. Unexpectedly increased lipoprotein (Lp)(a) also appear to contribute to the unusual responsiveness scenario. Identification of these responses and mechanisms underlying them are essential for effective management of LDL-C and cardiovascular risk. In this review, we describe plausible reasons underlying this phenomenon supported by findings of clinical trials. We also elaborate on the need for education and regular follow-up to improve adherence. Collectively, the review provides a summary of the past, present, and future of mechanisms and countermeasures revolving around unusual responses to PCSK9i therapy.
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Affiliation(s)
- Mingqi Ouyang
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, NO.139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Chenyu Li
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, NO.139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Die Hu
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, NO.139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, NO.139 Middle Renmin Road, Changsha 410011, Hunan, China
| | - Bilian Yu
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Research Institute of Blood Lipid and Atherosclerosis, Central South University, NO.139 Middle Renmin Road, Changsha 410011, Hunan, China.
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13
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Marku A, Da Dalt L, Galli A, Dule N, Corsetto P, Rizzo AM, Moregola A, Uboldi P, Bonacina F, Marciani P, Castagna M, Catapano AL, Norata GD, Perego C. Pancreatic PCSK9 controls the organization of the β-cell secretory pathway via LDLR-cholesterol axis. Metabolism 2022; 136:155291. [PMID: 35981632 DOI: 10.1016/j.metabol.2022.155291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Cholesterol is central to pancreatic β-cell physiology and alterations of its homeostasis contribute to β-cell dysfunction and diabetes. Proper intracellular cholesterol levels are maintained by different mechanisms including uptake via the low-density lipoprotein receptor (LDLR). In the liver, the proprotein convertase subtilisin/kexin type 9 (PCSK9) routes the LDLR to lysosomes for degradation, thus limiting its recycling to the membrane. PCSK9 is also expressed in the pancreas and loss of function mutations of PCSK9 result in higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Aim of this study was to investigate whether PCSK9 also impacts β-cells function. METHODS Pancreas-specific Pcsk9 null mice (Pdx1Cre/Pcsk9 fl/fl) were generated and characterized for glucose tolerance, insulin release and islet morphology. Isolated Pcsk9-deficient islets and clonal β-cells (INS1E) were employed to characterize the molecular mechanisms of PCSK9 action. RESULTS Pdx1Cre/Pcsk9 fl/fl mice exhibited normal blood PCSK9 and cholesterol levels but were glucose intolerant and had defective insulin secretion in vivo. Analysis of PCSK9-deficient islets revealed comparable β-cell mass and insulin content but impaired stimulated secretion. Increased proinsulin/insulin ratio, modifications of SNARE proteins expression and decreased stimulated‑calcium dynamics were detected in PCSK9-deficient β-cells. Mechanistically, pancreatic PCSK9 silencing impacts β-cell LDLR expression and cholesterol content, both in vivo and in vitro. The key role of LDLR is confirmed by the demonstration that LDLR downregulation rescued the phenotype. CONCLUSIONS These findings establish pancreatic PCSK9 as a novel critical regulator of the functional maturation of the β-cell secretory pathway, via modulation of cholesterol homeostasis.
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Affiliation(s)
- Algerta Marku
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Lorenzo Da Dalt
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Alessandra Galli
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Nevia Dule
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Paola Corsetto
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Angela Maria Rizzo
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Annalisa Moregola
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Patrizia Uboldi
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Fabrizia Bonacina
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Paola Marciani
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Michela Castagna
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy
| | - Alberico Luigi Catapano
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy; IRCCS Multimedica Hospital, Sesto San Giovanni, 20099 Milan, Italy
| | - Giuseppe Danilo Norata
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy; Centro SISA per lo studio dell'Aterosclerosi, Ospedale Bassini, 20092 Cinisello Balsamo, Italy.
| | - Carla Perego
- Dept of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20134 Milan, Italy.
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14
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The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathophysiology of psoriasis and systemic lupus erythematosus. Postepy Dermatol Alergol 2022; 39:645-650. [PMID: 36090718 PMCID: PMC9454343 DOI: 10.5114/ada.2022.118919] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/01/2021] [Indexed: 11/29/2022] Open
Abstract
Inflammation and atherogenic dyslipidaemia are often observed in skin diseases and represent an increased risk of cardiovascular disorders. Proprotein convertase subtilisin/kexin type 9 plays an important role in the regulation of serum low-density lipoprotein cholesterol levels. Its biological role, however, seems to go much beyond the regulation of cholesterol metabolism. The article presents potential pathophysiological links between inflammatory process and lipid disorders based on the example of psoriasis and systemic lupus erythematosus.
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15
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Cure E, Cumhur Cure M. Strong relationship between cholesterol, low-density lipoprotein receptor, Na +/H + exchanger, and SARS-COV-2: this association may be the cause of death in the patient with COVID-19. Lipids Health Dis 2021; 20:179. [PMID: 34895256 PMCID: PMC8666266 DOI: 10.1186/s12944-021-01607-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.
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Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, 34200 Istanbul, Turkey
| | - Medine Cumhur Cure
- Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey
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16
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Cure E, Cumhur Cure M. Strong relationship between cholesterol, low-density lipoprotein receptor, Na +/H + exchanger, and SARS-COV-2: this association may be the cause of death in the patient with COVID-19. Lipids Health Dis 2021. [PMID: 34895256 DOI: 10.1186/s12944-021-01607-5.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.
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Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, 34200, Istanbul, Turkey.
| | - Medine Cumhur Cure
- Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey
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17
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Amatruda M, Gembillo G, Giuffrida AE, Santoro D, Conti G. The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:868. [PMID: 34577791 PMCID: PMC8467670 DOI: 10.3390/medicina57090868] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.
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Affiliation(s)
- Michela Amatruda
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
- Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Giovanni Conti
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
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18
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de Armas-Rillo L, Quevedo-Abeledo JC, de Vera-González A, González-Delgado A, García-Dopico JA, Jimenez-Sosa A, Rodríguez-Lozano C, González-Gay MA, Ferraz-Amaro I. Proprotein convertase subtilisin/kexin type 9 in the dyslipidaemia of patients with axial spondyloarthritis is related to disease activity. Rheumatology (Oxford) 2021; 60:2296-2306. [PMID: 33295631 DOI: 10.1093/rheumatology/keaa590] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/13/2020] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism and has been linked to cardiovascular (CV) risk. The purpose of the present study was to examine whether PCSK9 levels are related to abnormalities in the lipid profile and the development of atherosclerosis that occurs in patients with axial SpA (axSpA). METHODS We performed a cross-sectional study that encompassed 545 individuals; 299 patients with axSpA and 246 statin use-matched controls. PCSK9 and standard lipid profiles were analysed in patients and controls. Carotid intima-media thickness (cIMT) and carotid plaques were assessed in patients. A multivariable analysis, adjusted for standard CV risk factors, was performed to evaluate the influence of PCSK9 on axSpA-related dyslipidaemia and subclinical carotid atherosclerosis. RESULTS Total cholesterol, high-density lipoprotein and low density lipoprotein cholesterol, lipoprotein (a) and apolipoprotein A1 were significantly lower in axSpA patients than controls. PCSK9 serum levels [β coefficient -44 ng/dl (95% CI -60, -27), P = 0.000] were also downregulated in axSpA patients after fully multivariable adjustment. ASDAS-CRP was found to be independently and significantly related to PCSK9 [β coefficient 10 ng/dl (95% CI 1, 18), P = 0.023] after analysing fully adjusted models that took age, sex and the rest of the lipid profile molecules into account. Whereas patients taking prednisone showed higher serum levels of PCSK9 [55 ng/ml (95% CI 24, 8), P = 0.001], those under anti-TNF-α therapies exhibited lower levels [β coefficient -26 ng/ml (95% CI -43, -9], P = 0.003]. CONCLUSION PCSK9 is downregulated in patients with axSpA. Disease activity is positive and significantly related to PSCK9. Anti-TNF-therapy yields a reduction in PCSK9 serum levels.
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Affiliation(s)
| | | | | | | | - José A García-Dopico
- Central Laboratory Division, Hospital Universitario de Canarias, Tenerife, Spain
| | | | | | - Miguel A González-Gay
- Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.,Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.,School of Medicine, University of Cantabria, Santander, Spain.,Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Iván Ferraz-Amaro
- Division of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
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19
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Barale C, Melchionda E, Morotti A, Russo I. PCSK9 Biology and Its Role in Atherothrombosis. Int J Mol Sci 2021; 22:ijms22115880. [PMID: 34070931 PMCID: PMC8198903 DOI: 10.3390/ijms22115880] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022] Open
Abstract
It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.
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MESH Headings
- Antibodies, Monoclonal, Humanized/therapeutic use
- Atherosclerosis/drug therapy
- Atherosclerosis/enzymology
- Atherosclerosis/genetics
- Atherosclerosis/pathology
- Blood Platelets/drug effects
- Blood Platelets/enzymology
- Blood Platelets/pathology
- Cholesterol, LDL/antagonists & inhibitors
- Cholesterol, LDL/metabolism
- Dyslipidemias/drug therapy
- Dyslipidemias/enzymology
- Dyslipidemias/genetics
- Dyslipidemias/pathology
- Fibrinolytic Agents/therapeutic use
- Gene Expression Regulation
- Humans
- Hypolipidemic Agents/therapeutic use
- Lipid Metabolism/drug effects
- Lipid Metabolism/genetics
- PCSK9 Inhibitors
- Plaque, Atherosclerotic/drug therapy
- Plaque, Atherosclerotic/enzymology
- Plaque, Atherosclerotic/genetics
- Plaque, Atherosclerotic/pathology
- Platelet Activation/drug effects
- Proprotein Convertase 9/biosynthesis
- Proprotein Convertase 9/genetics
- RNA, Small Interfering/therapeutic use
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- Signal Transduction
- Thrombosis/enzymology
- Thrombosis/genetics
- Thrombosis/pathology
- Thrombosis/prevention & control
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20
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Screening of PCSK9 and LDLR genetic variants in Familial Hypercholesterolemia (FH) patients in India. J Hum Genet 2021; 66:983-993. [PMID: 33864011 DOI: 10.1038/s10038-021-00924-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 11/09/2022]
Abstract
Familial Hypercholesterolemia (FH) is an autosomal, dominant, inherited disorder characterized by severely elevated LDL-cholesterol (LDL-C) levels with high risk for Coronary Artery Disease (CAD). There are limited genetic studies especially on genes other than Low Density Lipoprotein receptor (LDLR) conducted in Indian population. Thus, our aim was to screen the entire Proprotein Convertase Subtilisin/Kexin type 9 gene (PCSK9) gene & hotspot exons 3, 4 and 9 of LDLR gene in FH cases and controls. 50 FH cases were categorized into definite, probable and possible cases according to Dutch Lipid Network Criteria (DLNC) who were gender matched with 50 healthy controls. All 12 exons of PCSK9, and hotspot exons 3, 4 & 9 of LDLR gene were screened through High Resolution Melt (HRM) curve analysis. Enzyme linked immunosorbent assay was performed to measure circulating PCSK9 levels. Total cholesterol and LDL-C were significantly high in all three groups of cases. Total 8 nonpathogenic variants in exon 1, 5, 7 and 9 of the PCSK9 gene were detected. In LDLR gene, 3 known pathogenic and 1 benign variant were found in exon 3 & 4. In FH cases, PCSK9 levels were significantly high compared to controls (P = 0.0001), and were directly correlated to LDL-C (P = 0.0001) and Total Cholesterol (P = 0.0001). Our study is first to screen the entire PCSK9 gene in western part of India. Since no pathogenic variants were identified, it is possible that PCSK9 variants are clinically less relevant. However, 3 known pathogenic variants were found in the LDLR gene. These findings support our understanding of the genetic spectrum of FH in India.
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21
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Sánchez-Pérez H, Quevedo-Abeledo JC, Tejera-Segura B, de Armas-Rillo L, Rúa-Figueroa I, González-Gay MA, Ferraz-Amaro I. Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus. Ther Adv Musculoskelet Dis 2020; 12:1759720X20975904. [PMID: 33294038 PMCID: PMC7705780 DOI: 10.1177/1759720x20975904] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease
that regulates cholesterol metabolism through low-density lipoprotein
receptor degradation and that has been linked to cardiovascular (CV)
disease. The purpose of the present study was to examine whether PCSK9
levels are disrupted compared with controls in patients with systemic lupus
erythematosus (SLE). We additionally sought to establish whether PCSK9 is
related to both the abnormalities in the lipid profile and to the disease
activity or damage of patients with SLE. Methods: We performed a cross-sectional study that encompassed 366 individuals: 195
SLE patients and 171 age-, sex-, and statin intake-matched controls. PCSK9,
lipoproteins serum concentrations, and lipid profiles were assessed in
patients and controls. A multivariable analysis, adjusted for standard CV
risk factors, was performed to evaluate the role of PCSK9 in SLE-related
dyslipidemia. Results: Most lipid related-molecules were decreased in patients with SLE compared
with controls. This downregulation included PCSK9, with PCSK9 levels being
lower in patients than controls in the full multivariable analysis,
including the modifications in lipid profiles that the disease itself
produces {beta coefficient –73 [95% confidence interval (CI) –91 to –54]
ng/ml, p ⩽ 0.001}. Both SLICC and SLEDAI scores were
independently and positively related to PCSK9. Patients currently on
hydroxychloroquine exhibited decreased levels of PCSK9 compared with those
that were not taking hydroxychloroquine [beta coefficient –30 (95% CI −54 to
−6) ng/ml, p = 0.015]. Conclusion: PCSK9 is downregulated in SLE compared with controls, but SLE patients with
higher disease activity and damage exhibited higher PSCK9 serum levels.
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Affiliation(s)
| | | | - Beatriz Tejera-Segura
- Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Canarias, Spain
| | | | - Iñigo Rúa-Figueroa
- Division of Rheumatology, Hospital Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | - Miguel A González-Gay
- Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Cardenal Herrera Oria s/n, Santander, 39008, Spain
| | - Iván Ferraz-Amaro
- Division of Rheumatology, Hospital Universitario de Canarias, Ofra sn, Santa Cruz de Tenerife, 38320, Spain
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22
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Zhang B, Yang W, Wang S, Liu R, Loor JJ, Dong Z, Zhao Y, Ma X, Xia C, Xu C. Lipid Accumulation and Injury in Primary Calf Hepatocytes Challenged With Different Long-Chain Fatty Acids. Front Vet Sci 2020; 7:547047. [PMID: 33195520 PMCID: PMC7607255 DOI: 10.3389/fvets.2020.547047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 09/14/2020] [Indexed: 12/11/2022] Open
Abstract
Fatty liver disease is one of the most common disorders afflicting dairy cows during the postpartum period, and is associated with increased blood non-esterified fatty acid (NEFA) uptake by the liver. Major long-chain fatty acids (LCFA) in NEFA are palmitic (PA), palmitoleic (POA), stearic (SA), oleic (OA), and linoleic (LA) acid. In order to investigate the characteristics of lipid accumulation and injury caused by these NEFA, primary calf hepatocytes were isolated and challenged for 12 h with 1.2 mmol/L PA, POA, SA, OA, LA, or a mixture of these LCFA (NEFA). Compared with POA, OA, and LA, culture with PA and SA led to greater abundance of CCAAT-enhancer binding protein, glucose-regulated protein 78 mRNA, and stearoyl-CoA desaturase 1 mRNA along with greater concentrations of H2O2, malondialdehyde and reactive oxygen species (ROS). Although culture with POA, OA, and LA led to lower very low density lipoprotein (VLDL) concentration in cell culture medium, POA and OA led to greater concentrations of triacylglycerol, protein abundance of sterol regulatory element-binding protein 1c, fatty acid synthase, acetyl coenzyme A carboxylase 1, ApoB100, and sortilin 1 (SORT1). Compared with individual fatty acids, culture with NEFA led to an intermediate degree of lipid accumulation and hepatocytes damage. Overall, the data suggest that saturated fatty acids cause more severe oxidative and ER stress. However, unsaturated fatty acids cause serious lipid accumulation. Furthermore, a fatty acid balanced nutrient regulation was suggested useful improve liver health of transition period dairy cows.
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Affiliation(s)
- Bingbing Zhang
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Wei Yang
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Shuang Wang
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Runqi Liu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Division of Nutritional Sciences, Department of Animal Sciences, University of Illinois, Urbana, IL, United States
| | - Zhihao Dong
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yingying Zhao
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xinru Ma
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Cheng Xia
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Chuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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23
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Sobati S, Shakouri A, Edalati M, Mohammadnejad D, Parvan R, Masoumi J, Abdolalizadeh J. PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD). Adv Pharm Bull 2020; 10:502-511. [PMID: 33062601 PMCID: PMC7539318 DOI: 10.34172/apb.2020.062] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/29/2020] [Accepted: 02/02/2020] [Indexed: 12/14/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-density lipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it binds to LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLR expression is adjusted at the transcriptional level through sterol regulatory element binding protein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and the inducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing the concentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, the effect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniques that focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 have been proposed which concentrate on both extracellular and intracellular PCSK9, and they include blockage of PCSK9 production by using gene silencing agents and blockage of it's binding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tiny molecule inhibitors.
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Affiliation(s)
- Saeideh Sobati
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Amir Shakouri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Edalati
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Reza Parvan
- Department of Biosciences, University of Milan, Via celoria 26, 20133, Milan, Italy
| | - Javad Masoumi
- Immunology Department, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Jalal Abdolalizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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Small Interfering RNAs and RNA Therapeutics in Cardiovascular Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:369-381. [PMID: 32285425 DOI: 10.1007/978-981-15-1671-9_23] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ribonucleic acid (RNA) is being exploited and understood in its many aspects of function and structure for development of valuable tools in the therapeutics of various diseases such as cardiovascular etc. The expanded knowledge regarding function of RNA in the genomics and inside the cell has dramatically changed the therapeutic strategies in the past few years. RNA has become a spotlight of attention for developing novel therapeutic schemes and hence variety of therapeutic strategies is being coming into the picture that includes RNA interference, use of aptamers, role of microRNA (miRNA) that can alter the complex gene expression patterns. It is due to the fact that RNA offers various advantages in disease management as it can be edited and modified in its various forms such as secondary and tertiary structures. Although scientists are in process of manufacturing RNA-targeting therapies using variety of endogenous gene silencing regulators, Small interfering RNAs (Si RNAs), aptamers and microRNA for cardiovascular diseases yet the development of a novel, risk free therapeutic strategy is a major challenge and need of the hour in cardiovascular medicine. In this regard these agents are required to overcome pleothra of barriers such as stability of drug targets, immunogenicity, adequate binding, targeted delivery etc. to become effective drugs. Recent years have witnessed the progress of RNA therapeutic strategies in cardiovascular diseases that are likely to significantly expand the cardiovascular therapeutic repertoire within the next decade. The present manuscript has been compiled to summarize various approaches of siRNA based therapies in cardiovascular diseases along with the advantages, outcomes and limitations if any in this regard. In addition, the future prospects of RNA therapeutic modalities in cardiovascular diseases are summarized.
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25
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Flora GD, Nayak MK. A Brief Review of Cardiovascular Diseases, Associated Risk Factors and Current Treatment Regimes. Curr Pharm Des 2020; 25:4063-4084. [PMID: 31553287 DOI: 10.2174/1381612825666190925163827] [Citation(s) in RCA: 240] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/16/2019] [Indexed: 12/22/2022]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature death and disability in humans and their incidence is on the rise globally. Given their substantial contribution towards the escalating costs of health care, CVDs also generate a high socio-economic burden in the general population. The underlying pathogenesis and progression associated with nearly all CVDs are predominantly of atherosclerotic origin that leads to the development of coronary artery disease, cerebrovascular disease, venous thromboembolism and, peripheral vascular disease, subsequently causing myocardial infarction, cardiac arrhythmias or stroke. The aetiological risk factors leading to the onset of CVDs are well recognized and include hyperlipidaemia, hypertension, diabetes, obesity, smoking and, lack of physical activity. They collectively represent more than 90% of the CVD risks in all epidemiological studies. Despite high fatality rate of CVDs, the identification and careful prevention of the underlying risk factors can significantly reduce the global epidemic of CVDs. Beside making favorable lifestyle modifications, primary regimes for the prevention and treatment of CVDs include lipid-lowering drugs, antihypertensives, antiplatelet and anticoagulation therapies. Despite their effectiveness, significant gaps in the treatment of CVDs remain. In this review, we discuss the epidemiology and pathology of the major CVDs that are prevalent globally. We also determine the contribution of well-recognized risk factors towards the development of CVDs and the prevention strategies. In the end, therapies for the control and treatment of CVDs are discussed.
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Affiliation(s)
- Gagan D Flora
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, United States
| | - Manasa K Nayak
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, United States
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26
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Abstract
PURPOSE OF REVIEW Proprotein convertase subtilisin kexin 9 (PCSK9) plays a crucial role in regulating circulating levels of LDL-C as a consequence of its ability to inhibit LDL receptor recycling in the liver. Loss of function variants in the PCSK9 gene result in low LDL-C levels and associate with reduced cardiovascular risk, whereas gain of-function variants associate with hypercholesterolemia and increased risk of early cardiovascular events. Thus, PCSK9 inhibition has been established as an additional approach for the treatment of hypercholesterolemia. The aim of this review is to provide a brief overview of current strategies targeting PCSK9 and discuss clinical results of the emerging approaches. RECENT FINDINGS Two monoclonal antibodies targeting circulating PCSK9 (evolocumab and alirocumab) have been approved for the treatment of hypercholesterolemia and cardiovascular disease. Later, a gene silencing approach (inclisiran), which inhibits hepatic PCSK9 synthesis, was shown to be as effective as monoclonal antibodies but with a twice a year injection and is currently under evaluation for approval. Due to the elevated costs of such therapies, several other approaches have been explored, including peptide-based anti PCSK9 vaccination, and small oral PCSK9 inhibitors, which are still in preclinical phase. In the coming years, we will assist to a progressive introduction of novel anti-PCSK9 approaches in the clinical practice for the treatment of patients with hypercholesterolemia as well as patients at high cardiovascular risk.
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Affiliation(s)
- Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.,IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Angela Pirillo
- IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy.,Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
| | - Giuseppe D Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. .,Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy.
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27
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Strilchuk L, Tocci G, Fogacci F, Cicero AFG. An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia. Expert Opin Pharmacother 2020; 21:531-539. [DOI: 10.1080/14656566.2020.1714028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Larysa Strilchuk
- Department of Therapy and Medical Diagnostics, Lviv National Medical University, Lviv, Ukraine
| | - Giuliano Tocci
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University of Rome Sapienza, Sant’Andrea Hospital, Rome, Italy
- Cardiology Unit, IRCCS Neuromed, Pozzilli, Italy
| | - Federica Fogacci
- Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Arrigo F. G. Cicero
- Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy
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28
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Yang W, Liu R, Xia C, Chen Y, Dong Z, Huang B, Li R, Li M, Xu C. Effects of different fatty acids on BRL3A rat liver cell damage. J Cell Physiol 2020; 235:6246-6256. [PMID: 32012270 DOI: 10.1002/jcp.29553] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 01/10/2020] [Indexed: 12/15/2022]
Abstract
To evaluate the effects of fatty acids on endoplasmic reticulum (ER) stress, oxidative stress, and lipid damage. We treated BRL3A rat liver cells with, linoleic (LA), linolenic, oleic (OA), palmitic (PA), palmitoleic (POA), or stearic (SA) acid for 12 hr. The characteristics of cell lipid deposition, oxidative stress indexes, ER stress markers, nuclear factor κB p65 (NF-κB p65), lipid synthesis and transport regulators, and cholesterol metabolism regulators were analyzed. Endoplasmic chaperones like glucose-regulated protein 78, CCAAT-enhancer-binding protein, NF-κB p65, hydrogen peroxide, and malonaldehyde in PA- and SA-treated cells were significantly higher than in other treated cells. Deposition of fatty acids especially LA and POA were significantly increased than in other treated cells. De novo lipogenesis regulators sterol regulatory element-binding protein 1c, fatty acid synthase, and acetyl-coenzyme A carboxylase 1 (ACC1) expression were significantly increased in all fatty acid stimulation groups, and PA- and SA-treated cells showed lower p-ACC1 expression and higher scd1 expression than other fatty acid groups. Very low-density lipoprotein synthesis and apolipoprotein B100 expression in free fatty acids treated cells were significantly lower than control. PA, SA, OA, and POA had shown significantly increased cholesterol synthesis than other treated cells. PA and SA showed the lower synthesis of cytochrome P7A1 and total bile acids than other fatty acids treated cells. Excess of saturated fatty acids led to severe ER and oxidative stress. Excess unsaturated fatty acids led to increased lipid deposition in cultured hepatocytes. A balanced fatty acid intake is needed to maintain lipid homeostasis.
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Affiliation(s)
- Wei Yang
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Runqi Liu
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Cheng Xia
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yuanyuan Chen
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhihao Dong
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Baoyin Huang
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Ruirui Li
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Ming Li
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Chuang Xu
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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29
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Picard C, Poirier A, Bélanger S, Labonté A, Auld D, Poirier J, on behalf of the PREVENT-AD Research Group. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study. PLoS One 2019; 14:e0220254. [PMID: 31437157 PMCID: PMC6705826 DOI: 10.1371/journal.pone.0220254] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/11/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.
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Affiliation(s)
- Cynthia Picard
- Douglas Mental Health University Institute, Montréal, Québec, Canada
- Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, Québec, Canada
- Department of Psychiatry, McGill University, Montréal, Québec, Canada
| | - Alexandre Poirier
- Douglas Mental Health University Institute, Montréal, Québec, Canada
| | | | - Anne Labonté
- Douglas Mental Health University Institute, Montréal, Québec, Canada
- Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, Québec, Canada
| | - Daniel Auld
- Génome Québec Innovation Centre, Montréal, Québec, Canada
| | - Judes Poirier
- Douglas Mental Health University Institute, Montréal, Québec, Canada
- Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, Québec, Canada
- Department of Psychiatry, McGill University, Montréal, Québec, Canada
| | - on behalf of the PREVENT-AD Research Group
- Douglas Mental Health University Institute, Montréal, Québec, Canada
- Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, Québec, Canada
- Department of Psychiatry, McGill University, Montréal, Québec, Canada
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30
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Baiyisaiti A, Wang Y, Zhang X, Chen W, Qi R. Rosa rugosa flavonoids exhibited PPARα agonist-like effects on genetic severe hypertriglyceridemia of mice. JOURNAL OF ETHNOPHARMACOLOGY 2019; 240:111952. [PMID: 31100436 DOI: 10.1016/j.jep.2019.111952] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 04/22/2019] [Accepted: 05/09/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rosa rugosa Thunb. is a traditional Chinese medicine that was used in the treatment of cardiovascular diseases and relative risk factors such as diabetes, hyperlipidemia, hypertension, and inflammation. Rosa rugosa flavonoids (RRFs) are the main components in Rosa rugosa Thunb. Several studies have demonstrated that RRFs can regulate plasma lipid contents, but the related mechanism of which has not yet been elucidated clearly. AIM OF THE STUDY The goal of this study was to clarify the effects of RRFs on triglyceride metabolism and its related mechanisms. MATERIALS AND METHODS RRFs were obtained by ethanol extraction from Rosa rugosa Thunb.. Transgenic mice expressing human Apolipoprotein C3 (ApoC3) were used as a mouse model of hypertriglyceridemia. Fenofibrate (FNB), a PPARα agonist, was used as a positive control drug of decreasing high triglyceride. FNB (100 mg/kg) or RRFs (300 mg/kg) were given to the mice by gavage daily. Two weeks later, the changes of plasma lipid levels in the mice were measured by commercial kits, the clearance of triglyceride was evaluated by oral fat load test, and expression of the genes related to lipid β-oxidation and synthesis was detected in the mice livers by real time PCR. RESULTS RRFs, as well as FNB, were found to significantly reduce plasma triglyceride (TG) levels in ApoC3 transgenic mice after administration of the drug for two weeks. Plasma lipid clearance rate was increased and lipid content in the mice livers was reduced after administration of RRF. Treatment with RRFs up-regulated mRNA expression of PPARα and its downstream gene of ACOX, while down-regulated mRNA expression of the genes related to fatty acid synthesis (FASN, SREBP-1c, and ACC1). The expression of LPL was raised, while the expression of ApoC3 was decreased, and Foxo1 was inhibited by RRFs in the mice livers. CONCLUSION RRFs can reduce plasma TG levels by repressing the expression of ApoC3 and inducing the expression of LPL in liver. RRFs could also reduce triglyceride in hepatocytes through increasing β-oxidation and decreasing synthesis of the lipids. These findings show the potency of further clinical application of RRFs as a hypolipidemic drug for treatment of cardiovascular diseases.
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Affiliation(s)
- Asiya Baiyisaiti
- School of Pharmacy, Shihezi University, 832000, Xinjiang, China; Peking University Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
| | - Yuhui Wang
- Peking University Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Peking University, Beijing, 100191, China.
| | - Xuehui Zhang
- School of Pharmacy, Shihezi University, 832000, Xinjiang, China; Peking University Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
| | - Wen Chen
- School of Pharmacy, Shihezi University, 832000, Xinjiang, China.
| | - Rong Qi
- School of Pharmacy, Shihezi University, 832000, Xinjiang, China; Peking University Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
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31
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Casula M, Olmastroni E, Boccalari MT, Tragni E, Pirillo A, Catapano AL. Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials. Pharmacol Res 2019; 143:143-150. [PMID: 30926528 DOI: 10.1016/j.phrs.2019.03.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/15/2019] [Accepted: 03/25/2019] [Indexed: 12/15/2022]
Abstract
The therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors efficiently reduces plasma cholesterol levels, which has been recently associated with improvement in cardiovascular outcomes. This meta-analysis aimed at investigating the safety and efficacy of treatment with the clinically available anti-PCSK9 monoclonal antibodies (mAbs) in all published randomized clinical trials (RCTs), updating the available results with the recently published ODYSSEY OUTCOMES trial. Data search was carried out using PubMed/MEDLINE and EMBASE (inception - January 2019). Inclusion criteria were: (1) phase 2 or 3 RCTs; (2) comparing anti-PCSK9 mAbs (specifically evolocumab and alirocumab) with placebo; (3) with effects on outcomes reported; (4) with treatment duration longer than 8 weeks. Odds ratios (ORs) with 95% CIs were used as summary statistics. We pooled the estimates by using both the DerSimonian & Laird method (random-effects model). Between-study heterogeneity was tested by Cochrane's Q test and measured with the I2 statistics. Twenty-eight RCTs comprising 62,281 participants (33,204 in the mAb arm, 29,077 in the placebo arm) were included in the meta-analysis. The treatment follow-up ranged from 8 weeks up to 208 weeks. Overall, no significant difference in all-cause mortality was observed between the two groups (OR 0.93 [95% CI, 0.85-1.03]). The treatment with an anti-PCSK9 mAb was associated with a significant reduction of CV events compared with placebo (OR 0.83 [95% CI, 0.78-0.87]), being the FOURIER and ODYSSEY OUTCOMES studies the major contributors. Both myocardial infarction and stroke were significantly reduced following the treatment with an anti-PCSK9 mAb. No significant difference was observed in cardiovascular mortality (OR 0.94 [95% CI, 0.83-1.07]). The incidence of serious adverse events was similar in the two groups (OR: 0.95, [95% CI, 0.91-0.99]). Thus, the pharmacological approach with anti-PCSK9 mAbs significantly and safely improves cardiovascular outcomes. Despite that, the pooled analysis failed to show a significant cardiovascular mortality benefit with anti-PCSK9 mAb treatment, suggesting that specific longer-term studies are warranted to address this issue. We suggest that the observed delay between the rapid effect on plasma cholesterol levels and the emergence of the clinical benefit, observed both in FOURIER and ODYSSEY OUTCOMES trials, might explain this finding.
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Affiliation(s)
- Manuela Casula
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Elena Olmastroni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Mezio T Boccalari
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Elena Tragni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Angela Pirillo
- Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy.
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Brown M, Ahmed S. Emerging role of proprotein convertase subtilisin/kexin type-9 (PCSK-9) in inflammation and diseases. Toxicol Appl Pharmacol 2019; 370:170-177. [PMID: 30914377 DOI: 10.1016/j.taap.2019.03.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 12/17/2022]
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is most recognized serine protease for its role in cardiovascular diseases (CVD). PCSK9 regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by selectively targeting hepatic LDL receptors (LDLR) for degradation, thereby serving as a potential therapeutic target for CVD. New pharmacological agents under development aim to lower the risk of CVD by inhibiting PCSK9 extracellularly, although secondary effects of this approach are not yet studied. Here we review the history of PCSK9 and rationale behind developing inhibitors for CVD. Importantly, we summarized the studies investigating the role and impact of modulated PCSK9 levels in inflammation, specifically in sepsis, rheumatoid arthritis and other chronic inflammatory conditions. Furthermore, we summarized studies that investigated the interactions of PCSK9 with pro-inflammatory pathways, such as scavenger receptor CD36 and thrombospondin 1 (TSP-1) in inflammatory diseases. This review highlights the conflicting role that PCSK9 plays in different inflammatory disease states and postulates that any unwanted effects of PCSK9 inhibition in early clinical testing should critically be examined.
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Affiliation(s)
- Madalyn Brown
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
| | - Salahuddin Ahmed
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA; Division of Rheumatology, University of Washington School of Medicine, Seattle, WA, USA.
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Tarpley AJ. New Frontier in Lipids: PCSK9 Inhibitors and Implications for the Life Insurance Industry. J Insur Med 2019; 47:230-235. [PMID: 30789783 DOI: 10.17849/insm-47-4-1-6.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Since the Framingham Heart Study solidified cholesterol as a causative agent in the development of coronary heart disease there has been an explosion of research in the field of lipidology. Many therapeutic options have come and gone as we have been refining the goals of therapy to match the mortality outcome data of large clinical trials. A new frontier has emerged with the introduction of the PCSK9 inhibitors that are able with monthly injections to lower LDL cholesterol >60% with favorable side effect profiles and recently published favorable mortality data. This ushers in a whole new era of cholesterol management. Life insurance medical directors will need to be informed of how these drugs are being used and for conditions such as homozygous hypercholesterolemia, a condition with a very high mortality risk, and for new genetic analysis of affected patients, who are not as rare as once thought. This article provides the background about the development of these drugs, their expanded indications, how they may slip through the cracks of prescription drug (Rx) database inquiries, and touches on therapies in development beyond this class of medications. Medicine is an evolving field. With the new gene editing CRISPR technology it will truly be transformational for these genetically driven conditions with the potential for curative therapy. If curative therapy comes to pass it will, of course, have favorable implications for our evolving life insurance guidelines.
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Prochaska JH, Tröbs SO, Wild PS. PCSK9: A link between air pollution and cardiovascular disease? Eur J Prev Cardiol 2019; 26:576-577. [PMID: 30696261 DOI: 10.1177/2047487319827726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Jürgen H Prochaska
- 1 Preventive Cardiology and Preventive Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.,2 Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.,3 German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Germany
| | - Sven-Oliver Tröbs
- 3 German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Germany.,4 Center for Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Germany
| | - Philipp S Wild
- 1 Preventive Cardiology and Preventive Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.,2 Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.,3 German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Germany
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Genga KR, Lo C, Cirstea MS, Leitao Filho FS, Walley KR, Russell JA, Linder A, Francis GA, Boyd JH. Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors. EBioMedicine 2018; 38:257-264. [PMID: 30473376 PMCID: PMC6306489 DOI: 10.1016/j.ebiom.2018.11.032] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 12/22/2022] Open
Abstract
Background Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding Canadian Institutes of Health Research (PJT-156056).
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Affiliation(s)
- Kelly Roveran Genga
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
| | - Cody Lo
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - Mihai S Cirstea
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - Fernando Sergio Leitao Filho
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - Keith R Walley
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - James A Russell
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - Adam Linder
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Gordon A Francis
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
| | - John H Boyd
- Corresponding author at: Centre for Heart Lung Innovation, St. Paul's Hospital, Room 166 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada
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Auer J, Berent R. Alirocumab as add-on therapy to statins: current evidence and clinical potential. Ther Adv Cardiovasc Dis 2018; 12:191-202. [PMID: 29792380 DOI: 10.1177/1753944718775352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Atherosclerotic cardiovascular diseases (ASCVDs) are associated with a substantial mortality, physical morbidity, and mental disability. Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels play a major role in the pathophysiology of ASCVDs. Statins have been shown to reduce ASCVD risk and associated events and are recommended as first-line therapy for treatment of hypercholesterolemia by current international guidelines. The key issue is to attain guideline-recommended LDL-C levels (below 70 mg/dl) for patients at very high cardiovascular risk. However, many high-risk and very-high-risk patients on statin therapy remain beyond treatment goals despite lifestyle modification and statins, and are exposed to a high risk of future cardiovascular events including myocardial infarction (MI), stroke, revascularization procedures, and death. This clearly emphasizes the urgent need for additional LDL-C reduction with new therapeutic strategies to target these highly atherogenic particles and to further reduce the burden of ASCVDs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role as a key regulator of the hepatic LDL receptor recycling process. Developments over the past 15 years have demonstrated PCSK9 inhibition to be a novel therapeutic strategy to manage increased LDL-C levels. A number of clinical studies using humanized monoclonal antibody technology against PCSK9 have shown profound reductions of LDL-C levels when used either alone or in combination with statin therapy. Recently, the first cardiovascular outcome study demonstrated a significant reduction of ASCV events when evolocumab was added to a statin therapy. This review will discuss current knowledge about antibody-mediated PCSK9 inhibition as add-on therapy to statin and the clinical potential that may be expected.
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Affiliation(s)
- Johann Auer
- Department of Cardiology and Intensive Care, St Josef Hospital Braunau, Austria
| | - Robert Berent
- Center of Cardiovascular Rehabilitation, HerzReha Bad Ischl, Austria
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Li Z, Liu Q. Hepatitis C virus regulates proprotein convertase subtilisin/kexin type 9 promoter activity. Biochem Biophys Res Commun 2018; 496:1229-1235. [PMID: 29397939 DOI: 10.1016/j.bbrc.2018.01.176] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 01/29/2018] [Indexed: 12/11/2022]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease mainly expressed in liver. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, whether HCV regulates PCSK9 transcription has not been well studied. PCSK9 promoter activity is modulated by numerous transcription factors including sterol-regulatory element binding protein (SREBP)-1a, -1c, -2, hepatocyte nuclear factor-1 (HNF-1), and forkhead box O3 (FoxO3). Since they are differently regulated by HCV, we studied the effects of these transcription factors on PCSK9 promoter activity in the context of HCV infection and replication. We demonstrated that PCSK9 promoter activity was up-regulated after HCV infection and in HCV genomic replicon cells. We also studied the effects of HCV proteins on the PCSK9 promoter activity. While HCV structural proteins core, E1, and E2 had no effect, NS2, NS3, NS3-4A, NS5A and NS5B enhanced, and p7 and NS4B decreased PCSK9 promoter activity. Furthermore, we showed that transcription factors SREBP-1c, HNF-1α and specificity protein 1 increased PCSK9 promoter activity in HCV replicon cells, whereas SREBP-1a, HNF-1β and FoxO3 had an inhibitory effect. These results demonstrated the molecular mechanisms of how HCV modulates PCSK9 promoter activity and advanced our understanding on the mutual interactions between HCV and PCSK9.
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Affiliation(s)
- Zhubing Li
- VIDO-InterVac, Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- VIDO-InterVac, Vaccinology and Immunotherapeutics, Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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Li Z, Liu Q. Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. J Gen Virol 2017; 99:44-61. [PMID: 29235977 DOI: 10.1099/jgv.0.000987] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease actively involved in regulating lipid homeostasis. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, the underlying mechanisms have not been thoroughly characterized. Moreover, whether PCSK9 regulates HCV translation and assembly/secretion has not been determined. We therefore further studied the effects of PCSK9 on the HCV life cycle. We showed that PCSK9 did not affect HCV translation or assembly/secretion. Overexpression of PCSK9 inhibited HCV replication in HCV genomic replicon cells in a dose-dependent manner and after cell culture-derived HCV (HCVcc) infection. Knocking down PCSK9 increased HCV replication. The gain-of-function (D374Y) or loss-of-function (Δaa. 31-52) PCSK9 mutants for low-density lipoprotein receptor (LDLR) degradation had no effect on HCV replication, suggesting that HCV replication inhibition by PCSK9 was not due to LDLR degradation. The uncleaved ProPCSK9, but not cleaved PCSK9, down-regulated HCV replication, suggesting that the auto-cleavage of PCSK9 affected HCV replication. We also found that PCSK9 interacted with NS5A through NS5A aa. 95-215, and this region played an important role in NS5A dimerization, NS5A-RNA binding and was essential for HCV replication. More importantly, NS5A dimerization and NS5A-RNA binding were suppressed by PCSK9 upon interaction. These results suggested that PCSK9 inhibited HCV replication through interaction with NS5A. Our study should help optimize anti-HCV treatment regimen in patients with abnormal lipid profiles.
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Affiliation(s)
- Zhubing Li
- VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Alvi SS, Ansari IA, Ahmad MK, Iqbal J, Khan MS. Lycopene amends LPS induced oxidative stress and hypertriglyceridemia via modulating PCSK-9 expression and Apo-CIII mediated lipoprotein lipase activity. Biomed Pharmacother 2017; 96:1082-1093. [DOI: 10.1016/j.biopha.2017.11.116] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 11/20/2017] [Accepted: 11/20/2017] [Indexed: 12/18/2022] Open
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Wan H, Gumbiner B, Joh T, Riel T, Udata C, Forgues P, Garzone PD. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects. Clin Ther 2017; 39:2243-2259.e5. [DOI: 10.1016/j.clinthera.2017.09.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 08/28/2017] [Accepted: 09/15/2017] [Indexed: 01/08/2023]
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Affiliation(s)
- Stephan Gielen
- Klinikum Lippe, Klinik für Innere Medizin/Kardiologie, Angiologie und Internistische Intensivmedizin, Germany; and Martin-Luther-Universität Halle-Wittenberg, Medizinische Fakultät, Germany
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42
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Catapano AL, Pirillo A, Norata GD. Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives. Vasc Health Risk Manag 2017; 13:343-351. [PMID: 28919772 PMCID: PMC5590683 DOI: 10.2147/vhrm.s130338] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I–III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from −40% to −60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH.
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Affiliation(s)
- Alberico Luigi Catapano
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano.,IRCCS Multimedica Hospital, Sesto San Giovanni
| | - Angela Pirillo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano.,IRCCS Multimedica Hospital, Sesto San Giovanni
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano.,Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy.,School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
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Sultan Alvi S, Ansari IA, Khan I, Iqbal J, Khan MS. Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia. Free Radic Biol Med 2017; 108:394-403. [PMID: 28412198 DOI: 10.1016/j.freeradbiomed.2017.04.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 03/18/2017] [Accepted: 04/12/2017] [Indexed: 11/23/2022]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a serine protease of the proprotien convertase (PC) family that has profound effects on plasma low density lipoprotein cholesterol (LDL-C) levels, the major risk factor for coronary heart disease (CHD), through its ability to mediate LDL receptor (LDL-R) protein degradation and reduced recycling to the surface of hepatocytes. Thus, the current study was premeditated not only to evaluate the role of lycopene in targeting the inhibition of PCSK-9 via modulation of genes involved in cholesterol homeostasis in HFD rats but also to examine a correlation between HFD induced inflammatory cascades and subsequent regulation of PCSK-9 expression. Besides the effect of lycopene on hepatic PCSK-9 gene expression, PPI studies for PCSK-9-Lycopene complex and EGF-A of LDL-R were also performed via molecular informatics approach to assess the dual mode of action of lycopene in LDL-R recycling and increased removal of circulatory LDL-C. We for the first time deciphered that lycopene treatment significantly down-regulates the expression of hepatic PCSK-9 and HMGR, whereas, hepatic LDL-R expression was significantly up-regulated. Furthermore, lycopene ameliorated inflammation stimulated expression of PCSK-9 via suppressing the expression of inflammatory markers. The results from our molecular informatics studies confirmed that lycopene, while occupying the active site of PCSK-9 crystal structure, reduces the affinity of PCSK-9 to complex with EGF-A of LDL-R, whereas, atorvastatin makes PCSK-9-EGF-A complex formation more feasible than both of PCSK-9-EGF-A alone and Lycopene-PCSK-9-EGF-A complex. Based on above results, it can be concluded that lycopene exhibits potent hypolipidemic activities via molecular mechanisms that are either identical (HMGR inhibition) or distinct from that of statins (down-regulation of PCSK-9 mRNA synthesis). To the best of our knowledge, this is the first report that lycopene has this specific biological property. Being a natural, safer and alternative therapeutic agent, lycopene could be used as a complete regulator of cholesterol homeostasis and ASCVD.
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Affiliation(s)
- Sahir Sultan Alvi
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Irfan A Ansari
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Imran Khan
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Johar Iqbal
- Department of Biochemistry, Faculty of Medicine, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - M Salman Khan
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India.
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Ruscica M, Baragetti A, Catapano AL, Norata GD. Translating the biology of adipokines in atherosclerosis and cardiovascular diseases: Gaps and open questions. Nutr Metab Cardiovasc Dis 2017; 27:379-395. [PMID: 28237179 DOI: 10.1016/j.numecd.2016.12.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 12/14/2016] [Accepted: 12/16/2016] [Indexed: 01/10/2023]
Abstract
AIM Critically discuss the available data, to identify the current gaps and to provide key concepts that will help clinicians in translating the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases. DATA SYNTHESIS Adipose tissue is nowadays recognized as an active endocrine organ, a function related to the ability to secrete adipokines (such as leptin and adiponectin) and pro-inflammatory cytokines (tumor necrosis factor alpha and resistin). Studies in vitro and in animal models have observed that obesity status presents a chronic low-grade inflammation as the consequence of the immune cells infiltrating the adipose tissue as well as adipocytes. This inflammatory signature is often related to the presence of cardiovascular diseases, including atherosclerosis and thrombosis. These links are less clear in humans, where the role of adipokines as prognostic marker and/or player in cardiovascular diseases is not as clear as that observed in experimental models. Moreover, plasma adipokine levels might reflect a condition of adipokine-resistance in which adipokine redundancy occurs. The investigation of the cardio-metabolic phenotype of carriers of single nucleotide polymorphisms affecting the levels or function of a specific adipokine might help determine their relevance in humans. Thus, the aim of the present review is to critically discuss the available data, identify the current gaps and provide key concepts that will help clinicians translate the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases.
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Affiliation(s)
- M Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - A Baragetti
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; SISA Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy
| | - A L Catapano
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; IRCCS Multimedica Hospital, Sesto San Giovanni, Milan, Italy
| | - G D Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; SISA Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
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Zhang J, Long M, Yu Y. The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina. J Thorac Dis 2017; 9:1226-1233. [PMID: 28616272 DOI: 10.21037/jtd.2017.03.186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Blood lipid management is one of the effective strategies for coronary heart disease, and statins are the first-line lipid-lowering drugs. Low density lipoprotein cholesterol (LDL-C) drop brings about cardioprotective effects. Proprotein convertase subtilisin kexin type 9 (PCSK9) is known to increase LDL-C, thus hazarding LDL-C reduction-induced benefits. To date, how PCSK9 responds to various lipid-lowering strategies has not been fully clarified. METHODS This study involves patients with stable angina and aims to explore and clarify the short-term impacts of rosuvastatin and ezetimibe, alone or in combination, on circulating PCSK9. A total of 68 patients with stable angina were enrolled and 60 eligible patients were randomly assigned into 3 groups (20 subjects in each). Patients in different groups were treated for a period of 14 days with rosuvastatin 10 mg/d, ezetimibe 10 mg/d, and rosuvastatin 10 mg/d plus ezetimibe 10 mg/d, respectively. Concentrations of blood LDL-C and PCSK9 levels were measured at baseline and at the 14th day after treatment. RESULTS Both rosuvastatin and ezetimibe could reduce the LDL-C levels, and rosuvastatin displayed a stronger cholesterol-lowering effect than ezetimibe. Moreover, when combined, they yielded even greater efficacy in lowering LDL-C, as compared with either rosuvastatin or ezetimibe mono-treatment (P<0.05). Rosuvastatin therapy (alone or combined with ezetimibe) caused significant rise in circulating PCSK9. Nevertheless, no significant growth of PCSK9 levels (P=0.558) was observed during ezetimibe treatment. At the 14th day, no difference in PCKS9 levels was observed between the rosuvastatin group and the combination-therapy group (P=0.906). CONCLUSIONS Rosuvastatin plus ezetimibe therapy is more effective in reducing LDL-C levels as compared with either rosuvastatin or ezetimibe mono-medication. Meanwhile, such combination strategy does not further increase the levels of circulating PCSK9 compared to rosuvastatin mono-intervention, thus maintaining maximal clinical benefits from lipid-lowering.
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Affiliation(s)
- Jian Zhang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Mingzhi Long
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Yichao Yu
- The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
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Venomics analyses of the skin secretion of Dermatonotus muelleri : Preliminary proteomic and metabolomic profiling. Toxicon 2017; 130:127-135. [DOI: 10.1016/j.toxicon.2017.02.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 02/23/2017] [Accepted: 02/24/2017] [Indexed: 11/17/2022]
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Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol 2017; 9:76-91. [PMID: 28289523 PMCID: PMC5329749 DOI: 10.4330/wjc.v9.i2.76] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/23/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.
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Affiliation(s)
- Rahul Chaudhary
- Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States
| | - Jalaj Garg
- Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States
| | - Neeraj Shah
- Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States
| | - Andrew Sumner
- Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States
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[LDL-cholesterol and cardiovascular events: the lower the better?]. Wien Med Wochenschr 2016; 168:108-120. [PMID: 27770320 DOI: 10.1007/s10354-016-0518-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/23/2016] [Indexed: 10/20/2022]
Abstract
For over 30 years, intensive research efforts investigated the role of LDL cholesterol in the pathogenesis of cardiovascular disease. In various settings, large statin trials showed an association between LDL cholesterol levels and cardiovascular event rates. This association is often referred to as the 'LDL cholesterol hypothesis'. More recent trials on agents with totally different modes of action confirmed this association and indicated a causal relationship between lower LDL cholesterol levels and improved cardiovascular outcomes. It has been proposed to term this causal relationship the 'LDL cholesterol principle'. It is to be expected that currently ongoing outcomes trials will further support the assumption of a causal relationship and will finally offer an armamentarium to therapists that will enable individualized treatment of dyslipidemias and their sequelae.
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Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res 2016; 112:429-42. [PMID: 27496869 DOI: 10.1093/cvr/cvw194] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 07/06/2016] [Indexed: 12/17/2022] Open
Abstract
Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.
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Affiliation(s)
- Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy
| | - Hagai Tavori
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA
| | - Angela Pirillo
- Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy IRCCS Multimedica, Milan, Italy
| | - Sergio Fazio
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA
| | - Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy IRCCS Multimedica, Milan, Italy
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Ruscica M, Ferri N, Macchi C, Meroni M, Lanti C, Ricci C, Maggioni M, Fracanzani AL, Badiali S, Fargion S, Magni P, Valenti L, Dongiovanni P. Liver fat accumulation is associated with circulating PCSK9. Ann Med 2016; 48:384-91. [PMID: 27222915 DOI: 10.1080/07853890.2016.1188328] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) associates with cardiovascular disease independently of classic risk factors. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is secreted by hepatocytes and inhibits the uptake of low-density lipoproteins by targeting the receptor for degradation, and possibly lipogenesis. PCSK9 loss-of-function mutations and anti-PCKS9 drugs reduce LDL-cholesterol. AIM To evaluate whether hepatic fat content is associated with circulating PCSK9. MATERIALS AND METHODS In 201 consecutive patients biopsied for suspected nonalcoholic steatohepatitis, liver damage was quantified by NAFLD activity score, circulating PCSK9 by ELISA, and hepatic mRNA by qRT-PCR in a subset (n = 76). RESULTS Circulating PCSK9 was associated with steatosis grade (p = 0.0011), necroinflammation (p < 0.001), ballooning (p = 0.005), and fibrosis stage (p = 0.001). At multivariate analysis, PCSK9 was associated with steatosis grade (p = 0.012), older age and lower BMI, independently of sex, hyperglycemia, and fibrosis/inflammation. Circulating PCSK9 was associated with hepatic expression of SREBP-1c (p = 0.0002) and FAS (p = 0.03). PCSK9 mRNA levels were also correlated with steatosis severity (p = 0.04) and hepatic APOB (p < 0.001), SREBP-1c (p = 0.047) and FAS expression (p = 0.001). CONCLUSIONS Circulating PCSK9 increases with hepatic fat accumulation and correlates with the severity of steatosis, independently of metabolic confounders and liver damage. Modulation of PCSK9 synthesis and release might be involved in NAFLD pathogenesis. Key Messages Circulating PCSK9 levels increase with hepatic fat accumulation. Circulating PCSK9 levels are associated with increased de novo lipogenesis. Hepatic PCSK9 expression is associated with steatosis severity and activation of lipogenesis.
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Affiliation(s)
- Massimiliano Ruscica
- a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy
| | - Nicola Ferri
- b Department of Pharmaceutical and Pharmacological Sciences , Università di Padova , Padova , Italy
| | - Chiara Macchi
- a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy
| | - Marica Meroni
- c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy
| | - Claudia Lanti
- d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Chiara Ricci
- a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy
| | - Marco Maggioni
- e Department of Pathology , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Anna Ludovica Fracanzani
- c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;,d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Sara Badiali
- f Department of Surgery , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Silvia Fargion
- c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;,d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Paolo Magni
- a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy
| | - Luca Valenti
- c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;,d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
| | - Paola Dongiovanni
- d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy
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