Copyright (c) 2022 European Atherosclerosis Journal
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
- Articles
-
Published: August 31, 2022
Abstract
The Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) protease is a 692 amino acid glycoprotein which belongs to the proprotein convertase family. PCSK9 binds several receptors of the LDL family, including VLDLR, LRP1 but also with CD36, driving their lysosomal degradation. From the beginning of the 21st century a growing body of interest raised around the opportunity to pharmacologically inhibit PCSK9, and most recently, monoclonal antibodies have been successfully tested for the treatment of severe/genetic forms of dyslipidemia. Despite the majority of circulating PCSK9 being produced by the liver, other organs come into play contributing to its production, such as the heart, the pancreas, and the brain. Nonetheless, extrahepatic PCSK9 may exert a local/paracrine and or autocrine metabolic impact in the homeostatic regulation of cholesterol metabolism, suggesting that, opposite to the liver, in other tissue PCSK9 deficiency or inhibition could contribute to the development of specific organ and tissues dysfunctionalities.
Article Metrics Graph
References
- Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8):e153–639. https://doi.org/10.1161/CIR.0000000000001052
- Timmis A, Townsend N, Gale CP, Torbica A, Lettino M, Petersen SE, et al. European society of cardiology: Cardiovascular disease statistics 2019. Eur Heart J. 2020;41(1):12–85. https://doi.org/10.1093/eurheartj/ehz859
- Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science (80- ). 1986;232(4746):34–47. https://doi.org/10.1126/science.3513311
- Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81. Available from: http://dx.doi.org/10.1016/S0140-6736(10)61350-5
- Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455
- Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6. https://doi.org/10.1038/ng1161
- Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2010;208(1):177–82. https://doi.org/10.1016/j.atherosclerosis.2009.06.023
- Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Bélanger Jasmin S, Stifani S, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100(3):928–33. https://doi.org/10.1073/pnas.0335507100
- Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol. 2007;14(5):413–9. https://doi.org/10.1038/nsmb1235
- Poirier S, Mamarbachi M, Chen WT, Lee ASS, Mayer G. GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation. Cell Rep. 2015;13(10):2064–71. https://doi.org/10.1016/j.celrep.2015.11.006
- Lebeau P, Platko K, Al-Hashimi AA, Byun JH, Lhoták Š, Holzapfel N, et al. Loss-of-function PCSK9 mutants evade the unfolded protein response sensor GRP78 and fail to induce endoplasmic reticulum stress when retained. J Biol Chem. 2018;293(19):7329–43. https://doi.org/10.1074/jbc.RA117.001049
- Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R, Ly K, et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density Lipoprotein receptor degradation. Evidence for an intracellular route. J Biol Chem. 2009;284(42):28856–64. https://doi.org/10.1074/jbc.M109.037085
- Wang Y, Huang Y, Hobbs HH, Cohen JC. Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res. 2012;53(9):1932–43. https://doi.org/10.1194/jlr.M028563
- Lipari MT, Li W, Moran P, Kong-Beltran M, Sai T, Lai J, et al. Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels. J Biol Chem. 2012 Dec;287(52):43482–91. https://doi.org/10.1074/jbc.M112.380618
- Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem. 2008; https://doi.org/10.1074/jbc.M708098200
- Demers A, Samami S, Lauzier B, Des Rosiers C, Sock ETN, Ong H, et al. PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver. Arterioscler Thromb Vasc Biol. 2015; https://doi.org/10.1161/ATVBAHA.115.306032
- Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res. 2008;49(2):394–8. https://doi.org/10.1194/jlr.M700437-JLR200
- Dong B, Singh AB, Shende VR, Liu J. Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. Int J Mol Med. 2017 Mar;39(3):749–56. https://doi.org/10.3892/ijmm.2017.2879
- Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: Functional consequences of natural mutations and post-translational modifications. J Biol Chem. 2006;281(41):30561–72. https://doi.org/10.1074/jbc.M606495200
- Kosenko T, Golder M, Leblond G, Weng W, Lagace TA. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem. 2013 Mar;288(12):8279–88. https://doi.org/10.1074/jbc.M112.421370
- Peters DT, Henderson CA, Warren CR, Friesen M, Xia F, Becker CE, et al. Asialoglycoprotein receptor 1 is a specific cell-surface marker for isolating hepatocytes derived from human pluripotent stem cells. Dev. 2016;143(9):1475–81. https://doi.org/10.1242/dev.132209
- Chandler PG, Buckle AM. Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain. Cells. 2020;9(3). https://doi.org/10.3390/cells9030610
- Catapano AL, Pirillo A, Norata GD. New Pharmacological Approaches to Target PCSK9. Curr Atheroscler Rep. 2020;22(7). https://doi.org/10.1007/s11883-020-00847-7
- Schmidt AF, Swerdlow DI, Holmes M V., Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5(2):97–105. https://doi.org/10.1016/S2213-8587(16)30396-5
- Ye R, Onodera T, Scherer PE. Lipotoxicity and B cell maintenance in obesity and type 2 diabetes. J Endocr Soc. 2019;3(3):617–31. https://doi.org/10.1210/js.2018-00372
- Perego C, Da Dalt L, Pirillo A, Galli A, Catapano AL, Norata GD. Cholesterol metabolism, pancreatic β-cell function and diabetes. Biochimica et Biophysica Acta - Molecular Basis of Disease. 2019. https://doi.org/10.1016/j.bbadis.2019.04.012
- Da Dalt L, Ruscica M, Bonacina F, Balzarotti G, Dhyani A, Di Cairano E, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: The role of the low-density lipoprotein receptor. Eur Heart J. 2019;40(4):357–68. https://doi.org/10.1093/eurheartj/ehy357
- Schulze PC, Drosatos K, Goldberg IJ. Lipid use and misuse by the heart. Circ Res. 2016; https://doi.org/10.1161/CIRCRESAHA.116.306842
- Bharadwaj KG, Hiyama Y, Hu Y, Huggins LA, Ramakrishnan R, Abumrad NA, et al. Chylomicron- and VLDL-derived lipids enter the heart through different pathways: In vivo evidence for receptor- and non-receptor-mediated fatty acid uptake. J Biol Chem. 2010; https://doi.org/10.1074/jbc.M110.174458
- Carley AN, Bi J, Wang X, Banke NH, Dyck JRB, O’Donnell JM, et al. Multiphasic triacylglycerol dynamics in the intact heart during acute in vivo overexpression of CD36. J Lipid Res. 2013 Jan;54(1):97–106. https://doi.org/10.1194/jlr.M029991
- Schwinger RHG. Pathophysiology of heart failure. Cardiovasc Diagn Ther. 2021;11(1). https://doi.org/10.21037/CDT-20-302
- Kumar AA, Kelly DP, Chirinos JA. Mitochondrial Dysfunction in Heart Failure with Preserved Ejection Fraction. Circulation. 2019;139(11):1435–50. https://doi.org/10.1161/CIRCULATIONAHA.118.036259
- Pool L, Wijdeveld LFJM, de Groot NMS, Brundel BJJM. The role of mitochondrial dysfunction in atrial fibrillation: Translation to druggable target and biomarker discovery. Int J Mol Sci. 2021;22(16). https://doi.org/10.3390/ijms22168463
- Jubaidi FF, Zainalabidin S, Mariappan V, Budin SB. Mitochondrial dysfunction in diabetic cardiomyopathy: The possible therapeutic roles of phenolic acids. Int J Mol Sci. 2020;21(17):1–24. https://doi.org/10.3390/ijms21176043
- Da Dalt L, Castiglioni L, Baragetti A, Audano M, Svecla M, Bonacina F, et al. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction. Eur Heart J. 2021 Aug;42(32):3078–90. https://doi.org/10.1093/eurheartj/ehab431
- WU Q, TANG Z-H, PENG J, LIAO L, PAN L-H, WU C-Y, et al. The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer’s disease progression (Review). Biomed Reports. 2014;2(2):167–71. https://doi.org/10.3892/br.2013.213
- Kysenius K, Muggalla P, Mätlik K, Arumäe U, Huttunen HJ. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci. 2012 Jun;69(11):1903–16. https://doi.org/10.1007/s00018-012-0977-6
- Seidah NG, Mayer G, Zaid A, Rousselet E, Nassoury N, Poirier S, et al. The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol. 2008;40(6–7):1111–25. https://doi.org/10.1016/j.biocel.2008.01.030
- Adorni MP, Ruscica M, Ferri N, Bernini F, Zimetti F. Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease. Front Aging Neurosci. 2019;11:120. https://doi.org/10.3389/fnagi.2019.00120
- Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008;9(9):916–22. https://doi.org/10.1038/embor.2008.132
- Fang C, Luo T, Lin L. Elevation of serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations and its possible atherogenic role in patients with systemic lupus erythematosus. Ann Transl Med. 2018;6(23):452–452. https://doi.org/10.21037/atm.2018.11.04
- Zanni M V., Stone LA, Toribio M, Rimmelin DE, Robinson J, Burdo TH, et al. Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV. Open Forum Infect Dis. 2017;4(4). https://doi.org/10.1093/ofid/ofx227
- Zhang Y, Zhu CG, Xu RX, Li S, Guo YL, Sun J, et al. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J Clin Lipidol. 2014;8(5):494–500. https://doi.org/10.1016/j.jacl.2014.07.001
- Li S, Zhang Y, Xu RX, Guo YL, Zhu CG, Wu NQ, et al. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease. Ann Med. 2015;47(5):386–93. https://doi.org/10.3109/07853890.2015.1042908
- Bohula EA, Giugliano RP, Leiter LA, Verma S, Park JG, Sever PS, et al. Inflammatory and cholesterol risk in the FOURIER trial. Circulation. 2018;138(2):131–40. https://doi.org/10.1161/CIRCULATIONAHA.118.034032
- Clearfield M. C-reactive protein levels and outcomes after statin therapy. Curr Atheroscler Rep. 2006;8(1):8–9. https://doi.org/10.1056/nejmoa042378
- Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, Pacia S, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220(2):381–6. https://doi.org/10.1016/j.atherosclerosis.2011.11.026
- Ricci C, Ruscica M, Camera M, Rossetti L, MacChi C, Colciago A, et al. PCSK9 induces a pro-inflammatory response in macrophages. Sci Rep. 2018;8(1). https://doi.org/10.1038/s41598-018-20425-x
- Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, et al. Local effects of human PCSK9 on the atherosclerotic lesion. J Pathol. 2016;238(1):52–62. https://doi.org/10.1002/path.4630
- Tang ZH, Peng J, Ren Z, Yang J, Li TT, Li TH, et al. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis. 2017;262:113–22. https://doi.org/10.1016/j.atherosclerosis.2017.04.023
- Ammirati E, Cianflone D, Vecchio V, Banfi M, Vermi AC, De Metrio M, et al. Effector memory T cells are associated with atherosclerosis in humans and animal models. J Am Heart Assoc. 2012;1(1):27–41. https://doi.org/10.1161/JAHA.111.000125
- Mailer RKW, Gisterå A, Polyzos KA, Ketelhuth DFJ, Hansson GK. Hypercholesterolemia Enhances T Cell Receptor Signaling and Increases the Regulatory T Cell Population. Sci Rep. 2017;7(1). https://doi.org/10.1038/s41598-017-15546-8
- Westerterp M, Gautier EL, Ganda A, Molusky MM, Wang W, Fotakis P, et al. Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity. Cell Metab. 2017;25(6):1294-1304.e6. https://doi.org/10.1016/j.cmet.2017.04.005
- Ito A, Hong C, Oka K, Salazar J V., Diehl C, Witztum JL, et al. Cholesterol Accumulation in CD11c+ Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease. Immunity. 2016;45(6):1311–26. https://doi.org/10.1016/j.immuni.2016.11.008
- Bonacina F, Coe D, Wang G, Longhi MP, Baragetti A, Moregola A, et al. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation. Nat Commun. 2018 Aug 6; https://doi.org/10.1038/s41467-018-05322-1
- Li Y, Cam J, Bu G. Low-density lipoprotein receptor family: endocytosis and signal transduction. Mol Neurobiol. 2001 Feb;23(1):53–67. https://doi.org/10.1385/MN:23:1:53
- Norata GD, Caligiuri G, Chavakis T, Matarese G, Netea MG, Nicoletti A, et al. The Cellular and Molecular Basis of Translational Immunometabolism. Immunity. 2015;43(3):421–34. https://doi.org/10.1016/j.immuni.2015.08.023
- Liu X, Bao X, Hu M, Chang H, Jiao M, Cheng J, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020;588(7839):693–8. https://doi.org/10.1038/s41586-020-2911-7