Цель исследования. Работа посвящена исследованию динамики содержания окислительно модифицированных липопротеидов низкой плотности (ок-ЛПНП) в плазме крови, а также изучению изменения активности ключевых антиоксидантных ферментов в эритроцитах – Se-содержащей глутатионпероксидазы (GSH-Px), Cu,Zn-супероксиддисмутазы (СОД) и каталазы у больных ишемической болезнью сердца (ИБС) в процессе терапии ингибитором PCSK9 эволокумабом. Материалы и методы. В исследование включено 9 мужчин со стабильной ИБС в возрасте 59±10 лет, у которых имелось документированное подтверждение атеросклеротического поражения не менее одной магистральной коронарной артерии по данным коронароангиографии. Пациенты принимали стандартную терапию, включая антиагреганты, β-блокаторы и ингибиторы ангиотензинпревращающего фермента/антагонисты рецепторов ангиотензина, причем до начала исследования все принимали максимально переносимую дозу статинов. Поскольку за время терапии статинами не достигнуто целевых уровней холестерина (ХС) липопротеидов низкой плотности (ХС ЛПНП), пациентам назначена гиполипидемическая терапия с включением ингибитора PCSK9 эволокумаб фирмы Amgen в дозе 420 мг 1 раз в месяц. Содержание показателей липидного обмена определяли стандартными биохимическими методами. Уровень ок-ЛПНП в плазме крови определяли иммунохимическим методом. Активность антиоксидантных ферментов определяли в эритроцитах крови, используя биохимические методики. Результаты. Холестеринснижающий препарат нового типа – ингибитор protein convertase subtilisin/kexin типа 9 (PCSK9) эволокумаб (Amgen) не только эффективно снижает уровень ХС ЛПНП, но также значительно уменьшает содержание ок-ЛПНП в плазме крови. В отличие от статинов ингибитор PCSK9 не вызывает снижения активности антиоксидантных ферментов крови. Заключение. Ингибитор PCSK9 не влияет на параметры окислительного стресса.
Aim. We study the dynamics of oxidatively modified low-density lipoprotein (ox-LDL) content in blood plasma, as well as changes in the activity of key antioxidant enzymes such as Se-containing glutathione peroxidase (GSH-Px) Cu,Zn-superoxide dismutase (SOD) and catalase in erythrocytes of patients with coronary artery disease during treatment with PCSK9 inhibitor (ewolocumab). Materials and methods. The study included 9 men (59 ± 10 years) with coronary artery disease with atherosclerotic lesion at least one main coronary artery according to coronary angiography. Patients took standard therapy before taking the study, everyone took the maximum tolerated dose of statins. Since the target cholesterol levels of low-density lipoprotein cholesterol (LDL-C) were not achieved during the statin therapy, patients were prescribed lipid-lowering therapy with the inclusion of the inhibitor PCSK9-emocoucumab from Amgen 420 mg once a month. The content of lipid metabolism indices was determined by standard biochemical methods. The level of ox-LDL in the blood plasma was determined by the immunochemical method. The activity of antioxidant enzymes was determined in blood erythrocytes using biochemical techniques Results. Cholesterol-lowering drug of the new type – inhibitor protein convertase subtilisin/kexin type 9 (PCSK9) evolocumab (Amgen) not only effectively lowers the level of cholesterol in low density lipoprotein (LDL), but also significantly reduces the content of oxdatively modified LDL in blood plasma. Unlike statins, the inhibitor of PCSK9 does not cause a decrease in the activity of antioxidant enzymes of the blood. Conclusion. PCSK9 inhibitor has no effect on the parameters of oxidative stress.
1. Nawarskas JJ. HMG-CoA reductase inhibitors and coenzyme Q10. Cardiol Rev. 2005;13(2):76-9. https://doi.org/10.1097/01.crd. 0000154790. 42283.a1
2. Lankin VZ, Tikhaze AK, Kukharchuk VV, Konovalova GG, Pisarenko OI, Kaminnyi AI, Shumaev KB, Belenkov YN. Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins. Mol Cell Biochem. 2003;249(1-2):129-40. [Ланкин В.З., Тихазе А.К., Кухарчук В.В., Коновалова Г.Г., Писаренко О.И., Каминный А.И, Шумаев К.Б., Беленков Ю.Н. Антиоксиданты снижают интенсивность периоксидации in vivo липопротеинов низкой плотности при терапии статинами. Mol Cell Biochem. 2003; 249(1-2):129-40 (In Russ.)].
3. Lankin VZ, Tikhaze AK. Free radical lipoperoxidation during atherosclerosis and antioxidative therapy of this disease. In: Tomasi A., et al., eds. Free Radicals, Nitric Oxide and Inflammation: Molecular, Biochemical and Clinical Aspects. Amsterdam, etc.: IOS Press, NATO Science Series. 2003;344:218-31.
4. Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet. 2004;363(9412):892-4. https://doi.org/10.1016/S0140-6736(04)15739-5
5. Littlefield N, Beckstrand RL, Luthy KE. Statins' effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementation. J Am Assoc Nurse Pract. 2014;26(2):85-90. https://doi.10.1002/2327-6924.12046
6. Pisarenko OI, Studneva IM, Lankin VZ, Konovalova GG, Tikhaze AK, Kaminnaya VI, Belenkov YN. Inhibitor of beta-hydroxy-beta-methylglutaryl coenzyme A reductase decreases energy supply to the myocardium in rats. Bull Exp Biol Med. 2001;132(4):956-8.
7. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(12):2311-6. https://doi.org/10.1161/ATVBAHA.108.179697
8. Lankin VZ, Tikhaze AK. Role of Oxidative Stress in the Genesis of Atherosclerosis and Diabetes Mellitus: A Personal Look Back on 50 Years of Research. Сurr Аging Sci. 2017;10(1):18-25. https://doi.org/10.2174/ 1874609809666160926142640 [Ланкин В.З., Тихазе А.К. Роль окислительного стресса в генезе атеросклероза и сахарного диабета: личный взгляд на 50 лет исследований. Сurr Аging Sci. 2017;10(1):18-25. https://doi.org/10.2174/ 1874609809666160926142640]
9. Lankin VZ, Tikhaze AK, Konovalova GG, Kumskova EM, Shumaev KB. Aldehyde-dependent modification of low density lipoproteins. In: Handbook of Lipoprotein Research. NY. Nova Sci. 2010:85-107.
10. Pedersen TR. Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs. 2010;10 (Suppl 1):10-7. https://doi.org/10.2165/1158822-S0-000000000-00000
11. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23): 2531-40. https://doi.org/10.1016/j.jacc.2014.03.018
12. Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Kassahun H, Ruzza A, Ma Y, Somaratne R, Raal FJ. Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years from the Open-Label OSLER-1 Extension Study. JAMA Сardiol. 2017;2(6):598-607. https://doi.org/10.1001/jamacardio.2017. 0747
13. Viigimaa M, Abina J, Zemtsovskaya G, Tikhaze A, Konovalova G, Kumskova E, Lankin V. Malondialdehyde-modified low-density lipoproteins as biomarker for atherosclerosis. Blood Press. 2010;19(3):164-8. https://doi.org/10.3109/08037051.2010.484158
14. Lankin VZ, Konovalova GG, Tikhaze AK, Shumaev KB, Belova-Kumskova EM, Grechnikova MA, Viigimaa M. Aldehyde inhibition of antioxidant enzymes in blood of diabetic patients. J Diabetes. 2016;8(3):398-404. https://doi.org/10.1111/1753-0407.12309 [Ланкин В.З., Коновалова Г.Г, Тихазе А.К., Шумаев К.Б., Белова-Кумскова E.M., Гречникова М.А, Вийгимаа М. Альдегидное ингибирование антиоксидантных ферментов в крови пациентов с диабетом. J Diabetes. 2016;8(3):398-404. https://doi.org/10.1111/1753-0407.12309]
15. Chrysant SG. New onset diabetes mellitus induced by statins: current evidence. Postgrad Med. 2017;129(4):430-5. https://doi.org/10.1080/ 00325481.2017.1292107
________________________________________________
1. Nawarskas JJ. HMG-CoA reductase inhibitors and coenzyme Q10. Cardiol Rev. 2005;13(2):76-9. https://doi.org/10.1097/01.crd. 0000154790. 42283.a1
2. Lankin VZ, Tikhaze AK, Kukharchuk VV, Konovalova GG, Pisarenko OI, Kaminnyi AI, Shumaev KB, Belenkov YN. Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins. Mol Cell Biochem. 2003;249(1-2):129-40.
3. Lankin VZ, Tikhaze AK. Free radical lipoperoxidation during atherosclerosis and antioxidative therapy of this disease. In: Tomasi A., et al., eds. Free Radicals, Nitric Oxide and Inflammation: Molecular, Biochemical and Clinical Aspects. Amsterdam, etc.: IOS Press, NATO Science Series. 2003;344:218-31.
4. Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet. 2004;363(9412):892-4. https://doi.org/10.1016/S0140-6736(04)15739-5
5. Littlefield N, Beckstrand RL, Luthy KE. Statins' effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementation. J Am Assoc Nurse Pract. 2014;26(2):85-90. https://doi.10.1002/2327-6924.12046
6. Pisarenko OI, Studneva IM, Lankin VZ, Konovalova GG, Tikhaze AK, Kaminnaya VI, Belenkov YN. Inhibitor of beta-hydroxy-beta-methylglutaryl coenzyme A reductase decreases energy supply to the myocardium in rats. Bull Exp Biol Med. 2001;132(4):956-8.
7. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(12):2311-6. https://doi.org/10.1161/ATVBAHA.108.179697
8. Lankin VZ, Tikhaze AK. Role of Oxidative Stress in the Genesis of Atherosclerosis and Diabetes Mellitus: A Personal Look Back on 50 Years of Research. Сurr Аging Sci. 2017;10(1):18-25. https://doi.org/10.2174/ 1874609809666160926142640
9. Lankin VZ, Tikhaze AK, Konovalova GG, Kumskova EM, Shumaev KB. Aldehyde-dependent modification of low density lipoproteins. In: Handbook of Lipoprotein Research. NY. Nova Sci. 2010:85-107.
10. Pedersen TR. Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs. 2010;10 (Suppl 1):10-7. https://doi.org/10.2165/1158822-S0-000000000-00000
11. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23): 2531-40. https://doi.org/10.1016/j.jacc.2014.03.018
12. Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Kassahun H, Ruzza A, Ma Y, Somaratne R, Raal FJ. Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years from the Open-Label OSLER-1 Extension Study. JAMA Сardiol. 2017;2(6):598-607. https://doi.org/10.1001/jamacardio.2017. 0747
13. Viigimaa M, Abina J, Zemtsovskaya G, Tikhaze A, Konovalova G, Kumskova E, Lankin V. Malondialdehyde-modified low-density lipoproteins as biomarker for atherosclerosis. Blood Press. 2010;19(3):164-8. https://doi.org/10.3109/08037051.2010.484158
14. Lankin VZ, Konovalova GG, Tikhaze AK, Shumaev KB, Belova-Kumskova EM, Grechnikova MA, Viigimaa M. Aldehyde inhibition of antioxidant enzymes in blood of diabetic patients. J Diabetes. 2016;8(3):398-404. https://doi.org/10.1111/1753-0407.12309
15. Chrysant SG. New onset diabetes mellitus induced by statins: current evidence. Postgrad Med. 2017;129(4):430-5. https://doi.org/10.1080/ 00325481.2017.1292107
1 ФГБУ «Национальный медицинский исследовательский центр кардиологии» Минздрава России, Москва, Россия;
2 Центр кардиологии Таллиннского технологического университета, Таллинн, Эстония
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V.Z. LANKIN 1, A.K. TIKHAZE 1, M. VIIGIMAA 2, I.Е. CHAZOVA 1
1 FSBI "National Medical Research Cardiology Center" of the Ministry of Health of the Russian Federation, Moscow, Russia;
2 Center for Cardiology of Tallinn University of Technology, Tallinn, Estonia