PCSK9

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Structure of the PCSK9 protein

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease encoded by the PCSK9 gene. PCSK9 has a medical significance because it plays an important role in lipid homeostasis by promoting degradation of the LDL receptors responsible for clearing circulating LDL-cholesterol (LDL-C) from the plasma. Therefore, drugs that inhibit the actions of PCSK9 can theoretically lower the circulating cholesterol level, and thus lower the risk of developing cardiovascular disease.

Historical Perspective

PCSK9 was initially described as neural apoptosis-regulated convertase-1 (NARC-1), which is expressed in cells that have the capacity to proliferate and differentiate such as hepatocytes, kidney mesenchymal cells, colon epithelial cells, and embryonic brain telencephalon neurons.[1] The function of PCSK9 was first described in 2003 when a gain-of-function mutation of PCSK9 gene (leading to increased activity) was associated with familial hypercholesterolemia in 4 french families.[2] The association was further clarified in 2005 after the discovery of loss-of-function mutations of PCSK9 in patients with low LDL-C. This loss-of-function was linked to a 40% reduction in plasma levels of LDL-C in the studied population.[3]

Biochemistry

Structure

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease encoded by the PCSK9 gene in humans.[4] PCSK9 is a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.[5] PCSK9 gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase, and also plays a major regulatory role in cholesterol homeostasis.

Regulation

PCSK9 and LDL receptors are both mainly regulated by the transcription factor sterol-responsive element-binding protein 2 (SREBP2). SREBP2 is involved in a pathway also induced by statins[6] and by experimental resistin[7] which is an adipose-tissue derived adipokine. Another regulator of the PCSK9 gene expression is the hepatic nuclear factor 1 alpha (HNF1a), a transcription factor activated in the liver cells.[8]

Physiologic Function

Lipid Homeostasis

PCSK9 plays a major role in the metabolism of cholesterol. It binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR endocytosis and degradation in lysosomes. Reduced LDL receptor levels result in decreased metabolism of low density lipoprotein (LDL) and increased levels of circulating LDL.[9] The sterol regulatory element-binding protein-2 (SREBP-2), which is activated in the presence of low intracellular levels of cholesterol, induces the expression of PCSK9. This leads to a decrease in LDL cholesterol metabolism thereby restoring normal levels of circulating.[10]

PCSK9 function
PCSK9 function
Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408[11]

In addition to lowering LDL-C, PCSK9 deficiency has also been shown to lower cardiovascular risk factors by reducing postprandial hypertriglyceridemia.[12] PCSK9-deficient mice have also been demonstrated to have reduced lymphatic apoB secretion (the major lipoprotein of chylomicrons and LDL) as well as an increased ability to clear chylomicrons.[13]

Inflammation

PCSK9 is also an acute phase reactant whose expression increases in inflammatory states. The administration of lipopolysaccharide (LPS), an isolated bacterial protein that mimics acute infection or acute systemic inflammation, resulted in a 2.5-fold increase in PCSK9 mRNA levels and an increased PCSK9 expression in kidney tissues in mice.[14] In parallel, previous animal models have shown that LPS administration also produces an approximately 17-fold increase in LDL content of lysolecithin, a product derived from the oxidation of LDL.[15] These models have also been supported by studies showing strong association between inflammation and atherosclerosis in mice and hamsters. Although robust clinical data is still lacking, observational studies have shown an increased risk of coronary artery disease in patients with chronic inflammatory disorders. Furthermore, increased inflammatory markers are associated with adverse outcomes in patients with acute coronary syndromes. [16]

Apoptosis

Apoptotic cell death is one of the mechanisms implicated in the development of atherosclerosis. Oxidized LDL-induced apoptosis of human endothelial cells has been associated with an increased expression of PCSK9. Pretreatment of human endothelial cells with PCSK9-SiRNA (to inhibit PCSK9 expression) decreased LDL-induced apoptosis by reducing important mediators of apoptosis. PCSK9 reduced the Bcl-2/Bax ratio and inhibited the activation of both caspase 9 and 3.[17]

Blood Pressure Regulation

The epithelial Na+ channel (ENaC) regulates sodium homeostasis and plays a regulatory role in blood pressure control. It is a constitutively active ion-channel in the distal nephron responsible for active sodium reabsorption. Defects in ENaC are associated with essential forms of hereditary hypertension. PCSK9 was demonstrated to reduce ENaC protein expression in Xenopus epithelial cells by increasing endoplasmic reticulum-associated degradation and subsequently decreasing apical surface expression.[18]

Glucose Metabolism

Both PCSK9 and LDLR are expressed in insulin-producing pancreatic islet beta cells, and may be involved in the regulation of blood glucose. PCSK9-deficient mice were demonstrated to be hypoinsulinemic, hyperglycemic, and glucose-intolerant. Their islet cells exhibited signs of malformation, apoptosis and inflammation.[19] Nevertheless, the true effect of PCSK9 inhibition on glucose metabolism is unclear. The inhibition of PCSK9 by monoclonal antibodies had no significant effect on blood glucose and was not associated with worsening glycemic control in patients with diabetes.[20]

Adipose Tissue Metabolism

PCSK9-deficient mice were demonstrated to have adipocyte hypertrophy, increased in-vivo fatty acid uptake, and in-vitro triglyceride synthesis independent of LDL-receptors. Additionally, there was a 40-fold increase in cell surface levels of very-low-density lipoprotein receptors (VLDLR).[21] However, inhibition of PCSK9 by monoclonal antibodies was not demonstrated to increase central obesity.

PCSK9 Inhibitors

Elevated LDL cholesterol levels in the plasma have previously been associated with the development and progression of atherosclerosis, as well as an increased risk of myocardial infarction and stroke. LDL receptors, which are responsible for clearing LDL cholesterol from the circulation, get recycled back into the plasma membrane in order to bind more LDL. A novel approach to the management of dyslipidemia targets the inhibition of the serine protease PCSK9 leading to increased LDL receptor expression and increased LDL cholesterol clearance. [22][23][24][25]

Natural

  • Annexin A2 (AnxA2) is an endogenous compound that binds to the C-terminal domain of PCSK9 thereby preventing the interaction of PCSK9 with the LDL receptors particularly in the extrahepatic tissues. It has been demonstrated to be a functional inhibitor of PCSK9.[26]
  • Furin and PC5/6A are two proprotein convertases that cause proteolytic cleavage of the PCSK9 protein between the R218 and Q219 residues resulting in a defective enzyme. Furin was demonstrated to regulate PCSK9 mRNA levels in hepatocytes.[27]

Pharmacologic

Several drugs have been investigated for the inhibition of PCSK9, and have demonstrated a more potent lowering of LDL cholesterol levels than the current available drugs. It is biologically plausible that this reduction in LDL would also lead to a reduction in atherothrombotic events. Initial human trials have demonstrated good tolerability and efficacy in lowering LDL choleterol, but additional phase III clinical trials are ongoing to demonstrate the effect of PCSK9 inhibition on cardiovascular events and outcomes.[22][23][24][25]

Pharmacologic-interventions-for-PCSK9
Pharmacologic-interventions-for-PCSK9
Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408[11]

Monoclonal Antibodies

A number of monoclonal antibodies that bind to PCSK9 near the catalytic domain that interact with the LDL receptors, and hence inhibit the function of PCSK9 are currently in clinical trials. These include:

Other drugs being evaluated in phase I or II clinical trials include:

  • 1D05-IgG2 by Merck & Co. [33]
  • RG7652 by Roche/Genentech
  • LGT-209 by Novartis
  • 1B20 by Merck & Co.
  • J10, J16, J17 by Pfizer

Gene Silencing

Several agents work by shutting down the gene responsible for the synthesis of the PCSK9 protein.

  • PCSK9 antisense oligonucleotide (ISIS 394814) from Isis Pharmaceuticals has been demonstrated to increase the expression of the LDL receptors and decrease circulating total cholesterol levels in mice.[34]
  • Locked nucleic acids such as SPC4061 from Santaris Pharma demonstrated reduced PCSK9 mRNA levels when administered in mice.[35][36]
  • ALN-PCS by The Medicines Company and Alnylam Pharmaceuticals acts by means of RNA interference, which causes the gene to shut down production of the PCSK9 protein.[37][38] Two drugs are being tested: ALN-PCS02 administered intravenously and ALN-PCSsc administered subcutaneously.

Mimetic Peptides

PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of LDLR in order to induce its internalization and degradation. A mimetic peptide, which mimics the actions of EGF-A, was demonstrated to competitively inhibit PCSK9-mediated degradation of LDLR in HepG2 cells.[39] Examples of mimetic peptides currently being investigated include:

  • EGF-AB peptide fragment by Schering-Plough
  • LDLR (H306Y) subfragment by U.S. National Institute of Health
  • LDLR DNA construct by U.S. National Institute of Health

Adnectins

Adnectins are genetically engineered target-binding proteins designed bind therapeutic targets. They are similar to monoclonal antibodies including binding to targets with similar affinity and specificity, but differ in terms of sequence and lack of disulphide bonds in their single-domain structure.[40] The adnectin BMS-962476 by Bristol-Myers Squibb/Adnexus has recently completed its phase 1 clinical trial and demonstrated good tolerability with no notable safety signals.

Small-Molecule Inhibitors

Orally administered small-molecule inhibitors may act by altering the sequence of PCSK9 auto-catalytic intracellular processing, PCSK9 secretion, or LDL receptor interaction.[41] It has been also difficult to design a molecule that affects the flat and large target site of PCSK9 for LDL receptors.[42] Some small-molecule inhibitors in pre-clinical studies include:

  • SX-PCK9 by Serometrix
  • TBD by Shifa Biomedical

Cost-Effectiveness of Therapy

Praluent

Recently the FDA approved the drug Praluent (alirocumab) for patients who have heterozygous familial hypercholesterolemia (FH) and high-risk patients who have had a stroke or heart attack in the past and cannot take statins because of negative side effects. The drugs approval marks an important development in the combat of vascular disease. Doses are administered every two weeks with a cost of $40 a day or $14,600 a year, substantially higher than some generic statins, which can cost as little as $0.10 a day. Praluent is more expensive to manufacture than statins because they made in live genetically engineered cells. Manufacturers argue that the drugs are cost-effective because they will reduce medical costs of hospitalizations from stroke or heart attack and that the price of the drug reflects its value. Praluent used in combination with statins can lower cholesterol 40-70% [43] compared to statins that lower LDL an average of 40% [44]. Still, further research into the actual ability of the drug to reduce risk and complications is ongoing. Reduced prices and plans through insurers should help make the drug accessible to patients with lower ability to pay. Further research is needed to assess the cost-effectiveness of the medication, as Praluent may be a drug used for lifetime treatment. In addition to statins, alternative treatments are available for lowering cholesterol levels. Patients may undergo apheresis to remove LDL, but this treatment can be time consuming and expensive, at around $8,000 a month. Lomitapide and mipomersen are also medications that lower LDL, but with costs of $250,000 and $176,000 per year respectively many insurers do not cover the medications. Relative to alternative treatments for lowering LDL, patients with HF may find that Praluent is a cost-effective treatment option.

Repatha
                    Another PCSK9 inhibitor, Repatha (evolocumab), is approved for use in Europe and the FDA is scheduled to make a decision on the medication by August 27.  The drug was approved for adults with FH who cannot lower their LDL sufficiently with maximum dose statins for use in combination with statins or other lipid-lowering therapies. Repatha reduced LDL levels in patients by 61% compared to standard therapy alone [45]. Analysts estimate Repatha will cost about $3,750 per year outside of the US and could cost upwards of $10,000 in the US. This medication should reduce medical costs by reducing the number of hospitalizations for stroke or heart attack due to high LDL, but since the medication is intended for lifetime use, the costs are substantial. Further research into the cost-effectiveness of the drug, in terms of quality adjusted life years, is needed.

Clinical Significance of PCSK9 Inhibition

With the discovery of the PCSK9, many preclinical studies and clinical trials have reported the efficacy and safety of PCSK9 inhibition in lowering LDL cholesterol as add on agents or as monotherapy. However, certain questions regarding the long-term safety are still unanswered. Monoclonal antibodies against PCSK9 may elicit immunogenicity and immune-mediated responses. This may be reduced with the use of fully human monoclonal antibodies (e.g. evolocumab). Further studies are needed to determine the immunogenic effects of these agents and to demonstrate whether or not a risk of antidrug antibodies exists in these patients. [46] Additionally, most PCSK9 inhibitors are administered subcutaneously (few administered intravenously) and they require administration every 2 or 4 weeks raising concerns in regards to ease of use and compliance. Beyond the lowering of LDL cholesterol, the true added value of this class of drugs (PCSK9 inhibitors) can only be determined with large scale phase III trials that evaluate the efficacy of of this approach in the reduction of atherothrombotic events and improving clinical outcomes.

The combination of PCSK9 and statins has been of particular interest given the fact that statins have been demonstrated to increase the serum levels of PCSK9, thus affecting their LDL-C lowering capacity.[47][48] Subsequently, a statin-PSCK9 inhibitor would theoretically provide a synergistic effect on the reduction of serum levels of LDL cholesterol.

References

  1. ↑ Seidah, NG.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, SB.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc Natl Acad Sci U S A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMID 12552133. Unknown parameter |month= ignored (help)
  2. ↑ Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697. Unknown parameter |month= ignored (help)
  3. ↑ Cohen, J.; Pertsemlidis, A.; Kotowski, IK.; Graham, R.; Garcia, CK.; Hobbs, HH. (2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9". Nat Genet. 37 (2): 161–5. doi:10.1038/ng1509. PMID 15654334. Unknown parameter |month= ignored (help)
  4. ↑ Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. Unknown parameter |month= ignored (help)
  5. ↑ Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W. (2008). "Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration". Hepatology. 48 (2): 646–54. doi:10.1002/hep.22354. PMID 18666258. Unknown parameter |month= ignored (help)
  6. ↑ Lambert, G. (2007). "Unravelling the functional significance of PCSK9". Curr Opin Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605. Unknown parameter |month= ignored (help)
  7. ↑ Melone, M.; Wilsie, L.; Palyha, O.; Strack, A.; Rashid, S. (2012). "Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9". J Am Coll Cardiol. 59 (19): 1697–705. doi:10.1016/j.jacc.2011.11.064. PMID 22554600. Unknown parameter |month= ignored (help)
  8. ↑ Dong, B.; Wu, M.; Li, H.; Kraemer, FB.; Adeli, K.; Seidah, NG.; Park, SW.; Liu, J. (2010). "Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters". J Lipid Res. 51 (6): 1486–95. doi:10.1194/jlr.M003566. PMID 20048381. Unknown parameter |month= ignored (help)
  9. ↑ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". 2012-11-11.
  10. ↑ Maxwell, KN.; Soccio, RE.; Duncan, EM.; Sehayek, E.; Breslow, JL. (2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". J Lipid Res. 44 (11): 2109–19. doi:10.1194/jlr.M300203-JLR200. PMID 12897189. Unknown parameter |month= ignored (help)
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  13. ↑ Sun, H.; Samarghandi, A.; Zhang, N.; Yao, Z.; Xiong, M.; Teng, BB. (2012). "Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor". Arterioscler Thromb Vasc Biol. 32 (7): 1585–95. doi:10.1161/ATVBAHA.112.250043. PMID 22580899. Unknown parameter |month= ignored (help)
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  30. ↑ Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L; et al. (2012). "Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study". Lancet. 380 (9858): 1995–2006. doi:10.1016/S0140-6736(12)61771-1. PMID 23141812.
  31. ↑ Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D; et al. (2014). "Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial". JAMA. 311 (18): 1870–82. doi:10.1001/jama.2014.4030. PMID 24825642.
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  33. ↑ Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, Wang F; et al. (2011). "A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo". J Lipid Res. 52 (1): 78–86. doi:10.1194/jlr.M011445. PMC 2999929. PMID 20959675.
  34. ↑ Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (2007). "Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice". J. Lipid Res. 48 (4): 763–7. doi:10.1194/jlr.C600025-JLR200. PMID 17242417. Unknown parameter |month= ignored (help)
  35. ↑ Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM (2010). Deb, Sumitra, ed. "A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo". PLoS ONE. 5 (5): e10682. doi:10.1371/journal.pone.0010682. PMC 2871785. PMID 20498851.
  36. ↑ Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T (2012). "PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates". Mol. Ther. 20 (2): 376–81. doi:10.1038/mt.2011.260. PMC 3277239. PMID 22108858. Unknown parameter |month= ignored (help)
  37. ↑ "Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia". Press Release. BusinessWire. 2011-01-04. Retrieved 2011-01-04.
  38. ↑ Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K (2008). "Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11915–20. doi:10.1073/pnas.0805434105. PMC 2575310. PMID 18695239. Unknown parameter |month= ignored (help)
  39. ↑ Shan, L.; Pang, L.; Zhang, R.; Murgolo, NJ.; Lan, H.; Hedrick, JA. (2008). "PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide". Biochem Biophys Res Commun. 375 (1): 69–73. doi:10.1016/j.bbrc.2008.07.106. PMID 18675252. Unknown parameter |month= ignored (help)
  40. ↑ Lipovsek, D. (2011). "Adnectins: engineered target-binding protein therapeutics". Protein Eng Des Sel. 24 (1–2): 3–9. doi:10.1093/protein/gzq097. PMID 21068165. Unknown parameter |month= ignored (help)
  41. ↑ Do, RQ.; Vogel, RA.; Schwartz, GG. (2013). "PCSK9 Inhibitors: potential in cardiovascular therapeutics". Curr Cardiol Rep. 15 (3): 345. doi:10.1007/s11886-012-0345-z. PMID 23338726. Unknown parameter |month= ignored (help)
  42. ↑ Benjannet, S.; Hamelin, J.; Chrétien, M.; Seidah, NG. (2012). "Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation". J Biol Chem. 287 (40): 33745–55. doi:10.1074/jbc.M112.399725. PMID 22875854. Unknown parameter |month= ignored (help)
  43. ↑ Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M; et al. (2015). "Efficacy and safety of alirocumab in reducing lipids and cardiovascular events". N Engl J Med. 372 (16): 1489–99. doi:10.1056/NEJMoa1501031. PMID 25773378.
  44. ↑ Anand SS (2003). "Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Law MR, Wald NJ, Rudnicka AR. BMJ 2003; 326: 1407-408". Vasc Med. 8 (4): 289–90. PMID 15125495.
  45. ↑ Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J; et al. (2015). "Efficacy and safety of evolocumab in reducing lipids and cardiovascular events". N Engl J Med. 372 (16): 1500–9. doi:10.1056/NEJMoa1500858. PMID 25773607.
  46. ↑ Petrides F, Shearston K, Chatelais M, Guilbaud F, Meilhac O, Lambert G (2013). "The promises of PCSK9 inhibition". Curr Opin Lipidol. 24 (4): 307–12. doi:10.1097/MOL.0b013e328361f62d. PMID 23817198.
  47. ↑ Dubuc, G.; Chamberland, A.; Wassef, H.; Davignon, J.; Seidah, NG.; Bernier, L.; Prat, A. (2004). "Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia". Arterioscler Thromb Vasc Biol. 24 (8): 1454–9. doi:10.1161/01.ATV.0000134621.14315.43. PMID 15178557. Unknown parameter |month= ignored (help)
  48. ↑ Awan, Z.; Seidah, NG.; MacFadyen, JG.; Benjannet, S.; Chasman, DI.; Ridker, PM.; Genest, J. (2012). "Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial". Clin Chem. 58 (1): 183–9. doi:10.1373/clinchem.2011.172932. PMID 22065156. Unknown parameter |month= ignored (help)


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