Preview

The Russian Archives of Internal Medicine

Advanced search

СОХРАНЕНИЕ РЕЦЕПТОРОВ ЛПНП — НОВЫЙ ПОДХОД К ТЕРАПИИ ГИПЕРЛИПИДЕМИИ

https://doi.org/10.20514/2226-6704-2013-0-6-14-17

Abstract

LDL receptor plays a key role in the metabolism of LDL cholesterol. It have been shown that proprotein convertase subtlisin/kexin type 9 is essential for post-transcriptional regulatation of the cell surface expression of the LDL receptor by participating in its degradation. The data from large epidemiological studies indicate that persons with the loss-of-function mutations of PCSK9 have lower LDL level and CHD morbidity. Thus the development of biotechnical/pharmacological agents able to block PCSK9 can be the new option for treatment of patients with severe hyperlipidemia. Currently effectiveness of this approach is studied in large international randomized clinical trials.

About the Author

С. С. Бажан
ООО «Амджен»
Russian Federation
медицинский советник


References

1. Кухарчук В.В., Малышев П.П., Мешков А.Н. Семейная гиперхолестеринемия: современные аспекты диагностики, профилактики и терапии // Кардиология. 2009. № 49. С. 76–84.

2. Abifadel M., Varret M., Rabes J.P. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia // Nat. Genet. 2003. Vol. 34. P. 154–156.

3. Awan Z.N., Seidah G., MacFadyen J.G. et al. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial // Clin. Chem. 2012. Vol. 58. P. 183–189.

4. Ballantyne C.M., Abate N., Yuan Z. et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study // Am. Heart J. 2005. Vol. 149, № 3. P. 464–473.

5. Bruckert E., Hayem G., Dejager S. et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study // Cardiovasc. Drugs Ther. 2005. Vol. 19, № 6. P. 403–414.

6. Cohen J.C., Boerwinkle E., Mosley T.H. et al. Sequence variations in PCSK9, low LDL and protection against coronary heart disease // N. Engl. J. Med. 2006. Vol. 354. P. 1264–1272.

7. Dubuc G., Chamberland A., Wassef H. et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosisregulated convertase-1 implicated in familial hypercholesterolemia // Arterioscler. Thromb. Vasc. Biol. 2004. Vol. 24. P. 1454–1459.

8. Giugliano R.P., Desai N.R., Kohli P. et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study // Lancet. 2012. Vol. 380(9858). P. 2007–2017.

9. Goldstein J.L., Brown M.S. The LDL receptor // Arterioscler. Thromb. Vasc. Biol. 2009. Vol. 29. P. 431–438.

10. Koren M., Scott R., Kim J. et al. 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. 2012. Vol. 380(9858). P. 1995–2006.

11. Lambert G., Sjouke B., Choque B. et al. The PCSK9 decade // J. Lipid Res. 2012. Vol. 53, № 12. P. 2515–2524.

12. McKenney J.M., Koren M.J., Kereiakes D.J. et al.Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy // J. Am. Coll. Cardiol. 2012. Vol. 59, № 25. P. 2344–2353.

13. Naumova R.P., Tosi I., Patel D. et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: longterm follow-up and treatment response // Arterioscler. Thromb. Vasc. Biol. 2005. Vol. 25. P. 2654–2660.

14. Raal F., Scott R., Somaratne R. et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial // Circulation. 2012. Vol. 126, № 20. P. 2408–2417.

15. Seidah N.G., Benjannet S., Wickham L. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation // Proc. Natl. Acad. Sci. USA. 2003. Vol. 100. P. 928–933.

16. Stein E.A., Gipe D., Bergeron J., Gaudet D. et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial // Lancet. 2012. Vol. 380 (9836). P. 29–36.

17. Sullivan D., Olsson A.G., Scott R. et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statinintolerant patients: the GAUSS randomized trial // JAMA. 2012. Vol. 308, № 23. P. 2497–2506.

18. Welder G.I., Zineh M.A., Pacanowski J.S. et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol // J. Lipid Res. 2010. Vol. 51. P. 2714–2721.

19. Zaid A., Roubtsova A., Essalmani R. et al. Proprotein convertase subtilisin⁄ kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration // Hepatology. 2008. Vol. 48. P. 646–654.

20. Zhang D.W., Lagace T.A., Garuti R. et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation // J. Biol. Chem. 2007. Vol. 282. P. 18602–18612.


Review

For citations:


Бажан С.С. СОХРАНЕНИЕ РЕЦЕПТОРОВ ЛПНП — НОВЫЙ ПОДХОД К ТЕРАПИИ ГИПЕРЛИПИДЕМИИ. The Russian Archives of Internal Medicine. 2013;(6):14-17. (In Russ.) https://doi.org/10.20514/2226-6704-2013-0-6-14-17

Views: 757


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 2226-6704 (Print)
ISSN 2411-6564 (Online)