proprotein convertase 9

Summary

Summary: A proprotein convertase that is essential for CHOLESTEROL homeostasis. It binds to and is required for the lysosomal degradation of the LDL RECEPTOR (LDLR); the VLDL receptor, and the APOLIPOPROTEIN E RECEPTOR. It also regulates neuronal APOPTOSIS.

Top Publications

  1. Kastelein J, Hovingh G, Langslet G, Baccara Dinet M, Gipe D, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017;11:195-203.e4 pubmed publisher
    ..5%) and placebo groups (83.0%). In this large cohort of patients with HeFH, alirocumab significantly reduced LDL-C levels. Alirocumab was generally well tolerated. ..
  2. Ridker P, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med. 2017;376:1527-1539 pubmed publisher
    ..Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .). ..
  3. Zhang Y, Ultsch M, Skelton N, Burdick D, Beresini M, Li W, et al. Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists. Nat Struct Mol Biol. 2017;24:848-856 pubmed publisher
    ..Guided by structural information, we further engineered the identified groove-binding peptides into antagonists, which encroach on the EGF(A)-binding site and inhibit LDLR binding. ..
  4. Chadwick A, Wang X, Musunuru K. In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing. Arterioscler Thromb Vasc Biol. 2017;37:1741-1747 pubmed publisher
  5. Catapano A, Pirillo A, Norata G. Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives. Vasc Health Risk Manag. 2017;13:343-351 pubmed publisher
  6. Hadjiphilippou S, Ray K. PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: does reality match the hype?. Heart. 2017;103:1670-1679 pubmed publisher
    ..With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies. ..
  7. Krysa J, Ooi T, Proctor S, Vine D. Nutritional and Lipid Modulation of PCSK9: Effects on Cardiometabolic Risk Factors. J Nutr. 2017;147:473-481 pubmed publisher
  8. Sharifi M, Futema M, Nair D, Humphries S. Genetic Architecture of Familial Hypercholesterolaemia. Curr Cardiol Rep. 2017;19:44 pubmed publisher
    ..New genotyping methods such as next-generation sequencing will provide us with better understanding of the genetic architecture of FH. ..
  9. Cohen J, Hobbs H. Genetics. Simple genetics for a complex disease. Science. 2013;340:689-90 pubmed publisher

More Information

Publications56

  1. Bayes Genis A, Nunez J, Zannad F, Ferreira J, Anker S, Cleland J, et al. The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis. J Am Coll Cardiol. 2017;70:2128-2136 pubmed publisher
    ..Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression...
  2. Gong Y, Ma Y, Ye Z, Fu Z, Yang P, Gao B, et al. Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression. Metabolism. 2017;76:32-41 pubmed publisher
    ..We conclude a regulating role of TSH on hepatic PCSK9 expression, which further contributing to a higher LDL-c level. ..
  3. Murphy B, Tadin Strapps M, Jensen K, Mogg R, Liaw A, Herath K, et al. siRNA-mediated inhibition of SREBP cleavage-activating protein reduces dyslipidemia in spontaneously dysmetabolic rhesus monkeys. Metabolism. 2017;71:202-212 pubmed publisher
    ..These data demonstrate that a SCAP siRNA-LNP improved the lipid profile in a clinically relevant preclinical disease model and provide evidence for SCAP inhibition as a therapy for diabetic dyslipidemic patients. ..
  4. Skolnik N, Jaffa F, Kalyani R, Johnson E, Shubrook J. Reducing CV risk in diabetes: An ADA update. J Fam Pract. 2017;66:300-308 pubmed
    ..This Q&A highlights changes to the ADA's 2017 Standards of Care to help you fine-tune your approach to patients who have, or are at risk for, atherosclerotic CV disease. ..
  5. Ridker P, Tardif J, Amarenco P, Duggan W, Glynn R, Jukema J, et al. Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab. N Engl J Med. 2017;376:1517-1526 pubmed publisher
    ..Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .). ..
  6. Akram O, Bernier A, Petrides F, Wong G, Lambert G. Beyond LDL cholesterol, a new role for PCSK9. Arterioscler Thromb Vasc Biol. 2010;30:1279-81 pubmed publisher
  7. Schulz R, Schluter K. PCSK9 targets important for lipid metabolism. Clin Res Cardiol Suppl. 2017;12:2-11 pubmed publisher
    ..In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism. ..
  8. Ruotolo A, Di Taranto M, D Agostino M, Marotta G, Gentile M, Nunziata M, et al. The novel variant p.Ser465Leu in the PCSK9 gene does not account for the decreased LDLR activity in members of a FH family. Clin Chem Lab Med. 2014;52:e175-8 pubmed publisher
  9. Shen Y, Li H, Zhao L, Li G, Chen B, Guo Q, et al. Increased half-life and enhanced potency of Fc-modified human PCSK9 monoclonal antibodies in primates. PLoS ONE. 2017;12:e0183326 pubmed publisher
    ..These results demonstrate that Fc-modified anti-PCKS9 antibodies may enable less frequent or lower dosing of antibodies by improved recycling into the blood. ..
  10. Kumar S, Kang D, Rezvan A, Jo H. Accelerated atherosclerosis development in C57Bl6 mice by overexpressing AAV-mediated PCSK9 and partial carotid ligation. Lab Invest. 2017;97:935-945 pubmed publisher
    ..This accelerated model is well-suited to quickly determine the role of gene(s) interest without generating double or triple knockouts. ..
  11. Rodriguez Gutierrez R, Shah N, Montori V. Predicting the Overuse of PCSK-9 Inhibitors. JAMA. 2015;314:1909-10 pubmed publisher
  12. Schmidt A, Pearce L, Wilkins J, Overington J, Hingorani A, Casas J. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017;4:CD011748 pubmed publisher
    ..Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%). ..
  13. Schlegel V, Treuner Kaueroff T, Seehofer D, Berg T, Becker S, Ceglarek U, et al. Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease. PLoS ONE. 2017;12:e0181540 pubmed publisher
    ..The mean PCSK9 levels in the study population were much lower than those found in normal or healthy populations. Further studies are required to acquire a more detailed understanding of the role of PCSK9 in liver-related mortality. ..
  14. Sniderman A, Kiss R, Reid T, Thanassoulis G, Watts G. Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte. Clin Sci (Lond). 2017;131:791-797 pubmed publisher
    ..The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number. ..
  15. Giugliano R, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017;377:633-643 pubmed publisher
    ..Funded by Amgen; EBBINGHAUS ClinicalTrials.gov number, NCT02207634 .)...
  16. Pastori D, Nocella C, Farcomeni A, Bartimoccia S, Santulli M, Vasaturo F, et al. Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2017;70:1455-1462 pubmed publisher
    ..001). Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB2 suggests PCSK9 as a mechanism potentially implicated in platelet activation. ..
  17. Fahy E, McCarthy E, Steinhagen Thiessen E, Vaughan C. A case of autosomal recessive hypercholesterolemia responsive to proprotein convertase subtilisin/kexin 9 inhibition. J Clin Lipidol. 2017;11:287-288 pubmed publisher
    ..We report the first case of hypercholesterolemia due to autosomal recessive hyperlipidemia caused by LDLRAP1 mutation responding favorably to PCSK9 inhibition. ..
  18. Momtazi A, Banach M, Pirro M, Katsiki N, Sahebkar A. Regulation of PCSK9 by nutraceuticals. Pharmacol Res. 2017;120:157-169 pubmed publisher
    ..The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms. ..
  19. Baum S, Toth P, Underberg J, Jellinger P, Ross J, Wilemon K. PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers. Clin Cardiol. 2017;40:243-254 pubmed publisher
    ..This article reviews findings recognized and solutions suggested by experts during these discussions. The article is a product of the ASPC, along with each author writing as an individual and endorsed by the AACE. ..
  20. Amor Salamanca A, Castillo S, Gonzalez Vioque E, Dominguez F, Quintana L, Lluís Ganella C, et al. Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome. J Am Coll Cardiol. 2017;70:1732-1740 pubmed publisher
    ..FH clinical algorithms do not accurately classify patients with FH. Genetic testing should be advocated in young patients with ACS and high LDL-C levels to allow prompt identification of patients with FH and relatives at risk. ..
  21. Lee C, Lee Y, Park S, Kang S, Jang Y, Lee J, et al. Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels. PLoS ONE. 2017;12:e0186446 pubmed publisher
    ..The common novelty of variants suggested polymorphism of the two genes among them. Our results provide rare genetic information associated with this lipid phenotype in East Asian people. ..
  22. Sabatine M, Giugliano R, Keech A, Honarpour N, Wiviott S, Murphy S, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-1722 pubmed publisher
    ..Whether it prevents cardiovascular events is uncertain...
  23. Yla Herttuala S, Bentzon J, Daemen M, Falk E, Garcia Garcia H, Herrmann J, et al. Stabilization of atherosclerotic plaques: an update. Eur Heart J. 2013;34:3251-8 pubmed publisher
  24. Melendez Q, Krishnaji S, Wooten C, Lopez D. Hypercholesterolemia: The role of PCSK9. Arch Biochem Biophys. 2017;625-626:39-53 pubmed publisher
    ..The effects of PCSK9 on the LDL receptor, the relationship of this convertase with IDOL, and treatments currently available against hypercholesterolemia are also discussed. ..
  25. Disney M. Inhibiting Translation One Protein at a Time. Trends Biochem Sci. 2017;42:412-413 pubmed publisher
    ..Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. ..
  26. Grune J, Meyborg H, Bezhaeva T, Kappert K, Hillmeister P, Kintscher U, et al. PCSK9 regulates the chemokine receptor CCR2 on monocytes. Biochem Biophys Res Commun. 2017;485:312-318 pubmed publisher
    ..VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis. ..
  27. AlHajri L, AlHadhrami A, AlMheiri S, AlMutawa Y, AlHashimi Z. The efficacy of evolocumab in the management of hyperlipidemia: a systematic review. Ther Adv Cardiovasc Dis. 2017;11:155-169 pubmed publisher
    ..Hence, it provides an excellent alternative for patients with refractory disease or patients who develop intolerable side effects, therefore helping to overcome the stumbling block to achieving optimal lipid management. ..
  28. Dong B, Singh A, Shende V, Liu J. Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. Int J Mol Med. 2017;39:749-756 pubmed publisher
  29. Morena M, Le May C, Chenine L, Arnaud L, Dupuy A, Pichelin M, et al. Plasma PCSK9 concentrations during the course of nondiabetic chronic kidney disease: Relationship with glomerular filtration rate and lipid metabolism. J Clin Lipidol. 2017;11:87-93 pubmed publisher
    ..These data suggest that kidney function per se does not impact significantly PCSK9 metabolism. ..
  30. Chapman M, Blankenberg S, Landmesser U. The year in cardiology 2015: prevention. Eur Heart J. 2016;37:510-9 pubmed publisher
  31. Melendez Q, Wooten C, Lopez D. Atorvastatin and lovastatin, but not pravastatin, increased cellular complex formation between PCSK9 and the LDL receptor in human hepatocyte-like C3A cells. Biochem Biophys Res Commun. 2017;492:103-108 pubmed publisher
    ..These results may explain why Prav works better for statin intolerant patients than other statins such as Atorv and Lov. ..
  32. Liberale L, Montecucco F, Camici G, Dallegri F, Vecchie A, Carbone F, et al. Treatment with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes. Curr Med Chem. 2017;24:1403-1416 pubmed publisher
    ..In the next future, the improvement of the knowledge of the "pleiotropic" effects of PCSK9 inhibitors might unveil therapeutic potential on cardiovascular outcome independently on the cholesterol lowering activity. ..
  33. Levenson A, Milliren C, Biddinger S, Ebbeling C, Feldman H, Ludwig D, et al. Calorically restricted diets decrease PCSK9 in overweight adolescents. Nutr Metab Cardiovasc Dis. 2017;27:342-349 pubmed publisher
    ..Change in HOMA-IR was associated with change in PCSK9, independent of weight loss, suggesting an important relationship with insulin sensitivity. ClinicalTrials.gov Identifier: NCT01080339. ..
  34. Ray K, Landmesser U, Leiter L, Kallend D, Dufour R, Karakas M, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376:1430-1440 pubmed publisher
    ..Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .). ..
  35. Wanneh E, Luna G, Dufour R, Baass A. Predicting proprotein convertase subtilisin kexin type-9 loss of function mutations using plasma PCSK9 concentration. J Clin Lipidol. 2017;11:55-60 pubmed publisher
    ..This analysis suggests that plasma PCSK9 combined with LDL-C concentrations might be useful to predict certain PCSK9 LOF mutations such as the R46L mutation but may fail to predict others such as the InsLEU mutation. ..
  36. Sattar N, Toth P, Blom D, Koren M, Soran H, Uhart M, et al. Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus. Am J Cardiol. 2017;120:1521-1527 pubmed publisher
    ..Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment. ..
  37. Vogt A. Hyperlipoproteinaemia(a) - apheresis and emerging therapies. Clin Res Cardiol Suppl. 2017;12:12-17 pubmed publisher
    ..Currently LA is the standard of care as a last resort treatment in high-risk patients with elevated Lp(a) and severe CVD despite optimal control of all other cardiovascular risk factors. ..
  38. Everett B, Smith R, Hiatt W. Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015;373:1588-91 pubmed publisher
  39. Bang S, Chae H, Lee C, Choi H, Ryu J, Li W, et al. New Aromatic Compounds from the Fruiting Body of Sparassis crispa (Wulf.) and Their Inhibitory Activities on Proprotein Convertase Subtilisin/Kexin Type 9 mRNA Expression. J Agric Food Chem. 2017;65:6152-6157 pubmed publisher
    ..07, 7.18, 18.46, and 8.23 ?M, respectively (berberine, positive control, IC50 = 8.04 ?M), suggesting that compounds 1, 8, 11, and 14 are suitable for use in supplements to the statins for hyperlipidemia treatments. ..
  40. Fu T, Guan Y, Xu J, Wang Y. APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862:883-889 pubmed publisher
    ..Infusion of PCSK9 into WT mice also had no effect on the levels of hepatic APP, APLP2 or LRP1. Thus, APP, APLP2 and LRP1 are not required for PCSK9-mediated LDLR degradation and are not regulated by PCSK9 in vivo. ..
  41. Sun L, Yang X, Li Q, Zeng P, Liu Y, Liu L, et al. Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice. Arterioscler Thromb Vasc Biol. 2017;37:1290-1300 pubmed publisher
    ..However, ADP355 activated hepatic LDLR expression and ameliorated lipid metabolism in both types of mice and inhibited atherosclerosis in apoE-/- mice. ..
  42. Romagnuolo R, Scipione C, Marcovina S, Gemin M, Seidah N, Boffa M, et al. Roles of the low density lipoprotein receptor and related receptors in inhibition of lipoprotein(a) internalization by proprotein convertase subtilisin/kexin type 9. PLoS ONE. 2017;12:e0180869 pubmed publisher
    ..Our findings are consistent with the idea that PCSK9 inhibits Lp(a) clearance through the LDLR, but do not exclude other effects of PCSK9 such as on Lp(a) biosynthesis. ..
  43. Navarese E, Kolodziejczak M, Schulze V, Gurbel P, Tantry U, Lin Y, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163:40-51 pubmed publisher
    ..PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG. ..
  44. Jetty V, Glueck C, Lee K, Goldenberg N, Prince M, Kumar A, et al. Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ?70 mg/dL despite maximal-tolerated LDL-cholesterol-lowering therapy. Vasc Health Risk Manag. 2017;13:247-253 pubmed publisher
    ..Whether the health care savings arising from the anticipated reduction of CVD events by ALI or EVO justify their costs in populations with HeFH-CVD and LDLC >100 mg/dL despite MTDLLT remains to be determined. ..
  45. Benn M, Nordestgaard B, Frikke Schmidt R, Tybjærg Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. BMJ. 2017;357:j1648 pubmed publisher
  46. Ooi T, Krysa J, Chaker S, Abujrad H, Mayne J, Henry K, et al. The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response. J Clin Endocrinol Metab. 2017;102:3452-3460 pubmed publisher
    ..Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk. ..
  47. Pel P, Chae H, Nhoek P, Kim Y, Chin Y. Chemical Constituents with Proprotein Convertase Subtilisin/Kexin Type 9 mRNA Expression Inhibitory Activity from Dried Immature Morus alba Fruits. J Agric Food Chem. 2017;65:5316-5321 pubmed publisher
    ..All of the structures were established by NMR spectroscopic data as well as MS analysis. Of the isolates, moracin C (7) was found to inhibit PCSK9 mRNA expression with an IC50 value of 16.8 ?M in the HepG2 cells. ..