The Impact of PCSK9 on Risk Factors for Ischemic Stroke and Potential Mechanisms — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
The Impact of PCSK9 on Risk Factors for Ischemic Stroke and Potential Mechanisms
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
,
Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
1 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
2 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
3 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
4 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
5 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
6 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
7 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
8 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
9 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
10 Cerebrovascular Diseases Department, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), The First Affiliated Hospital of Faculty of Medicine Macau University of Science and Technology, Zhuhai, China
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PCs) family, which facilitates the degradation of low-density lipoprotein receptors (LDL-R) via intracellular and cell surface pathways, consequently elevating serum LDL-C levels. PCSK9 is implicated in various processes such as lipid metabolism, atherosclerosis, oxidative stress, inflammatory responses, thrombosis, and apoptosis. It is closely linked to ischemic stroke through its role in inducing and advancing atherosclerosis. PCSK9 inhibitors play a useful role in both acute and secondary prevention of ischemic stroke and can reduce the risk of ischemic stroke. This review examines the influence of PCSK9 on the risk factors associated with ischemic stroke and explores its potential mechanisms, and briefly describes the application of PCSK9 inhibitors in ischemic stroke.
KeywordsProprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)Ischemic StrokeAtherosclerosisInflammation
Norata, G.D., Tibolla, G. and Catapano, A.L. (2014) Targeting PCSK9 for Hypercholesterolemia. Annual Review of Pharmacology and Toxicology , 54, 273-293. https://doi.org/10.1146/annurev-pharmtox-011613-140025
Seidah, N.G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S.B., Stifani, S., et al . (2003) The Secretory Proprotein Convertase Neural Apoptosis-Regulated Convertase 1 (NARC-1): Liver Regeneration and Neuronal Differentiation. Proceedings of the National Academy of Sciences , 100, 928-933. https://doi.org/10.1073/pnas.0335507100
Sobati, S., Shakouri, A., Edalati, M., Mohammadnejad, D., Parvan, R., Masoumi, J., et al . (2020) PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD). Advanced Pharmaceutical Bulletin , 10, 502-511. https://doi.org/10.34172/apb.2020.062
Schmidt, R.J., Zhang, Y., Zhao, Y., Qian, Y., Wang, H., Lin, A., et al . (2008) A Novel Splicing Variant of Proprotein Convertase Subtilisin/Kexin Type 9. DNA and Cell Biology , 27, 183-189. https://doi.org/10.1089/dna.2007.0667
Welder, G., Zineh, I., Pacanowski, M.A., Troutt, J.S., Cao, G. and Konrad, R.J. (2010) High-Dose Atorvastatin Causes a Rapid Sustained Increase in Human Serum PCSK9 and Disrupts Its Correlation with LDL Cholesterol. Journal of Lipid Research , 51, 2714-2721. https://doi.org/10.1194/jlr.m008144
Bea, A.M., Perez-Calahorra, S., Marco-Benedi, V., Lamiquiz-Moneo, I., Jarauta, E., Mateo-Gallego, R., et al . (2017) Effect of Intensive LDL Cholesterol Lowering with PCSK9 Monoclonal Antibodies on Tendon Xanthoma Regression in Familial Hypercholesterolemia. Atherosclerosis , 263, 92-96. https://doi.org/10.1016/j.atherosclerosis.2017.06.009
Hopewell, J.C., Malik, R., Valdés-Márquez, E., Worrall, B.B. and Collins, R. (2017) Differential Effects of PCSK9 Variants on Risk of Coronary Disease and Ischaemic Stroke. European Heart Journal , 39, 354-359. https://doi.org/10.1093/eurheartj/ehx373
Wang, Y., Li, Z., Gu, H., Zhai, Y., Zhou, Q., Jiang, Y., et al . (2022) China Stroke Statistics: An Update on the 2019 Report from the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations. Stroke and Vascular Neurology , 7, 415-450. https://doi.org/10.1136/svn-2021-001374
Tu, W., Zhao, Z., Yin, P., Cao, L., Zeng, J., Chen, H., et al . (2023) Estimated Burden of Stroke in China in 2020. JAMA Network Open , 6, e231455. https://doi.org/10.1001/jamanetworkopen.2023.1455
Chao, B., Tu, W. and Wang, L. (2021) Initial Establishment of a Stroke Management Model in China: 10 Years (2011-2020) of Stroke Prevention Project Committee, National Health Commission. Chinese Medical Journal , 134, 2418-2420. https://doi.org/10.1097/cm9.0000000000001856
Wu, S., Wu, B., Liu, M., Chen, Z., Wang, W., Anderson, C.S., et al . (2019) Stroke in China: Advances and Challenges in Epidemiology, Prevention, and Management. The Lancet Neurology , 18, 394-405. https://doi.org/10.1016/s1474-4422(18)30500-3
Gu, X., Li, Y., Chen, S., Yang, X., Liu, F., Li, Y., et al . (2019) Association of Lipids with Ischemic and Hemorrhagic Stroke. Stroke , 50, 3376-3384. https://doi.org/10.1161/strokeaha.119.026402
Cao, Z., Li, S., Yang, H., Xu, C., Zhang, Y., Yang, X., et al . (2021) Associations of Behaviors, Biological Phenotypes and Cardiovascular Health with Risks of Stroke and Stroke Subtypes: A Prospective Cohort Study. EClinicalMedicine , 33, 100791. https://doi.org/10.1016/j.eclinm.2021.100791
Walter, K. (2022) What Is Acute Ischemic Stroke? JAMA , 327, 885. https://doi.org/10.1001/jama.2022.1420
Rashid, H., Meredith, I.T. and Nasis, A. (2017) PCSK9 Monoclonal Antibodies in 2016: Current Status and Future Challenges. Heart , Lung and Circulation , 26, 786-798. https://doi.org/10.1016/j.hlc.2016.12.005
Zhang, D., Lagace, T.A., Garuti, R., Zhao, Z., McDonald, M., Horton, J.D., et al . (2007) 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. Journal of Biological Chemistry , 282, 18602-18612. https://doi.org/10.1074/jbc.m702027200
Gouni-Berthold, I. (2015) PCSK9 Antibodies: A New Class of Lipid-Lowering Drugs. Atherosclerosis Supplements , 18, 21-27. https://doi.org/10.1016/j.atherosclerosissup.2015.02.003
Pirro, M., Bianconi, V., Francisci, D., Schiaroli, E., Bagaglia, F., Sahebkar, A., et al . (2017) Hepatitis C Virus and Proprotein Convertase Subtilisin/Kexin Type 9: A Detrimental Interaction to Increase Viral Infectivity and Disrupt Lipid Metabolism. Journal of Cellular and Molecular Medicine , 21, 3150-3161. https://doi.org/10.1111/jcmm.13273
Kwon, H.J., Lagace, T.A., McNutt, M.C., Horton, J.D. and Deisenhofer, J. (2008) Molecular Basis for LDL Receptor Recognition by Pcsk9. Proceedings of the National Academy of Sciences , 105, 1820-1825. https://doi.org/10.1073/pnas.0712064105
Yamamoto, T., Lu, C. and Ryan, R.O. (2011) A Two-Step Binding Model of PCSK9 Interaction with the Low Density Lipoprotein Receptor. Journal of Biological Chemistry , 286, 5464-5470. https://doi.org/10.1074/jbc.m110.199042
Surdo, P.L., Bottomley, M.J., Calzetta, A., Settembre, E.C., Cirillo, A., Pandit, S., et al . (2011) Mechanistic Implications for LDL Receptor Degradation from the PCSK9/LDLR Structure at Neutral pH. EMBO reports , 12, 1300-1305. https://doi.org/10.1038/embor.2011.205
Chorba, J.S., Galvan, A.M. and Shokat, K.M. (2018) Stepwise Processing Analyses of the Single-Turnover PCSK9 Protease Reveal Its Substrate Sequence Specificity and Link Clinical Genotype to Lipid Phenotype. Journal of Biological Chemistry , 293, 1875-1886. https://doi.org/10.1074/jbc.ra117.000754
Jang, H., Lee, S.E., Yang, J., Lee, H., Shin, D., Lee, H., et al . (2019) Cyclase-associated Protein 1 Is a Binding Partner of Proprotein Convertase Subtilisin/Kexin Type-9 and Is Required for the Degradation of Low-Density Lipoprotein Receptors by Proprotein Convertase Subtilisin/Kexin Type-9. European Heart Journal , 41, 239-252. https://doi.org/10.1093/eurheartj/ehz566
Baass, A., Dubuc, G., Tremblay, M., Delvin, E.E., O'Loughlin, J., Levy, E., et al . (2009) Plasma PCSK9 Is Associated with Age, Sex, and Multiple Metabolic Markers in a Population-Based Sample of Children and Adolescents. Clinical Chemistry , 55, 1637-1645. https://doi.org/10.1373/clinchem.2009.126987
Dubuc, G., Tremblay, M., Paré, G., Jacques, H., Hamelin, J., Benjannet, S., et al . (2010) A New Method for Measurement of Total Plasma PCSK9: Clinical Applications. Journal of Lipid Research , 51, 140-149. https://doi.org/10.1194/jlr.m900273-jlr200
Cui, Q., Ju, X., Yang, T., Zhang, M., Tang, W., Chen, Q., et al . (2010) Serum PCSK9 Is Associated with Multiple Metabolic Factors in a Large Han Chinese Population. Atherosclerosis , 213, 632-636. https://doi.org/10.1016/j.atherosclerosis.2010.09.027
Barale, C., Melchionda, E., Morotti, A. and Russo, I. (2021) PCSK9 Biology and Its Role in Atherothrombosis. International Journal of Molecular Sciences , 22, Article No. 5880. https://doi.org/10.3390/ijms22115880
D’Ardes, D., Santilli, F., Guagnano, M.T., Bucci, M. and Cipollone, F. (2020) From Endothelium to Lipids, through MicroRNAs and PCSK9: A Fascinating Travel across Atherosclerosis. High Blood Pressure & Cardiovascular Prevention , 27, 1-8. https://doi.org/10.1007/s40292-019-00356-y
Tavori, H., Giunzioni, I., Predazzi, I.M., Plubell, D., Shivinsky, A., Miles, J., et al . (2016) Human PCSK9 Promotes Hepatic Lipogenesis and Atherosclerosis Development via apoE-and LDLR-Mediated Mechanisms. Cardiovascular Research , 110, 268-278. https://doi.org/10.1093/cvr/cvw053
Libby, P., Ridker, P.M. and Hansson, G.K. (2011) Progress and Challenges in Translating the Biology of Atherosclerosis. Nature , 473, 317-325. https://doi.org/10.1038/nature10146
Xiao, J., Bai, X., Liao, L., Zhou, M., Peng, J., Xiang, Q., et al . (2019) Hydrogen Sulfide Inhibits PCSK9 Expression through the PI3K/Akt‑SREBP‑2 Signaling Pathway to Influence Lipid Metabolism in HepG2 Cells. International Journal of Molecular Medicine , 43, 2055-2063. https://doi.org/10.3892/ijmm.2019.4118
Lee, S., Lee, H., Kwon, Y., Lee, S.E., Cho, Y., Kim, J., et al . (2014) Adenylyl Cyclase-Associated Protein 1 Is a Receptor for Human Resistin and Mediates Inflammatory Actions of Human Monocytes. Cell Metabolism , 19, 484-497. https://doi.org/10.1016/j.cmet.2014.01.013
Hofmann, A., Brunssen, C. and Morawietz, H. (2018) Contribution of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 and LOX-1 Modulating Compounds to Vascular Diseases. Vascular Pharmacology , 107, 1-11. https://doi.org/10.1016/j.vph.2017.10.002
Iida, Y., Tanaka, H., Sano, H., Suzuki, Y., Shimizu, H. and Urano, T. (2018) Ectopic Expression of PCSK9 by Smooth Muscle Cells Contributes to Aortic Dissection. Annals of Vascular Surgery , 48, 195-203. https://doi.org/10.1016/j.avsg.2017.10.005
Chen, L., Yuan, T. and Xu, J. (2017) Relationship between Proprotein Convertase Subtilisin 9 and Atherosclerosis and Plaque Rupture. Molecular Biomedicine , 23, 4785-4790.
Li, J., Liang, X., Wang, Y., Xu, Z. and Li, G. (2017) Investigation of Highly Expressed PCSK9 in Atherosclerotic Plaques and ox-LDL-Induced Endothelial Cell Apoptosis. Molecular Medicine Reports , 16, 1817-1825. https://doi.org/10.3892/mmr.2017.6803
Wang, M., Guo, Y. and Chen, M. (2017) Correlation Analysis between Proprotein Convertase Subtilisin 9 Level and Inflammatory Factors in Patients with Coronary Heart Disease. Journal of Cardiopulmonary and Vascular Diseases , 36, 433-435.
Wang, Y., Ye, J., Li, J., Chen, C., Huang, J., Liu, P., et al . (2016) Polydatin Ameliorates Lipid and Glucose Metabolism in Type 2 Diabetes Mellitus by Downregulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Cardiovascular Diabetology , 15, Article No. 19. https://doi.org/10.1186/s12933-015-0325-x
Miao, J., Manthena, P.V., Haas, M.E., Ling, A.V., Shin, D., Graham, M.J., et al . (2015) Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9. Arteriosclerosis , Thrombosis , and Vascular Biology , 35, 1589-1596. https://doi.org/10.1161/atvbaha.115.305688
Costet, P., Cariou, B., Lambert, G., Lalanne, F., Lardeux, B., Jarnoux, A., et al . (2006) Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-Binding Protein 1c. Journal of Biological Chemistry , 281, 6211-6218. https://doi.org/10.1074/jbc.m508582200
Zhang, X., Yang, M. and Liang, D. (2018) Changes and Correlation of Serum Proprotein Convertase Subtilisin 9 Levels in Patients with Type 2 Diabetes. Basic Research , 43, 1153-1156.
Yang, S., Li, S., Zhang, Y., Xu, R., Guo, Y., Zhu, C., et al . (2015) Positive Correlation of Plasma PCSK9 Levels with HbA 1c in Patients with Type 2 Diabetes. Diabetes / Metabolism Research and Reviews , 32, 193-199. https://doi.org/10.1002/dmrr.2712
Müller-Wieland, D., Leiter, L.A., Cariou, B., Letierce, A., Colhoun, H.M., Del Prato, S., et al . (2017) Design and Rationale of the ODYSSEY DM-DYSLIPIDEMIA Trial: Lipid-Lowering Efficacy and Safety of Alirocumab in Individuals with Type 2 Diabetes and Mixed Dyslipidaemia at High Cardiovascular Risk. Cardiovascular Diabetology , 16, Article No. 70. https://doi.org/10.1186/s12933-017-0552-4
Jellinger, P.S., Handelsman, Y., Rosenblit, P.D., Bloomgarden, Z.T., Fonseca, V.A., Garber, A.J., et al . (2017) American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocrine Practice , 23, 1-87. https://doi.org/10.4158/ep171764.appgl
Peng, J., Liu, M., Jin, J., Cao, Y., Guo, Y., Wu, N., et al . (2020) Association of Circulating PCSK9 Concentration with Cardiovascular Metabolic Markers and Outcomes in Stable Coronary Artery Disease Patients with or without Diabetes: A Prospective, Observational Cohort Study. Cardiovascular Diabetology , 19, Article No. 209. https://doi.org/10.1186/s12933-020-01142-0
Tóth, Š., Fedačko, J., Pekárová, T., Hertelyová, Z., Katz, M., Mughees, A., et al . (2017) Elevated Circulating PCSK9 Concentrations Predict Subclinical Atherosclerotic Changes in Low Risk Obese and Non-Obese Patients. Cardiology and Therapy , 6, 281-289. https://doi.org/10.1007/s40119-017-0092-8
Giugliano, R.P., Desai, N.R., Kohli, P., Rogers, W.J., Somaratne, R., Huang, F., et al . (2012) 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. The Lancet , 380, 2007-2017. https://doi.org/10.1016/s0140-6736(12)61770-x
Milionis, H., Liamis, G. and Elisaf, M. (2014) Proprotein Convertase Subtilisin Kexin 9 Inhibitors: Next Generation in Lipid-Lowering Therapy. Expert Opinion on Biological Therapy , 15, 287-298. https://doi.org/10.1517/14712598.2015.984682
Ramin-Mangata, S., Wargny, M., Pichelin, M., Le May, C., Thédrez, A., Blanchard, V., et al . (2020) Circulating PCSK9 Levels Are Not Associated with the Conversion to Type 2 Diabetes. Atherosclerosis , 293, 49-56. https://doi.org/10.1016/j.atherosclerosis.2019.11.027
Shi, J., Zhang, W., Niu, Y., Lin, N., Li, X., Zhang, H., et al . (2020) Association of Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Levels and the Risk of Incident Type 2 Diabetes in Subjects with Prediabetes: A Population-Based Cohort Study. Cardiovascular Diabetology , 19, Article No. 167. https://doi.org/10.1186/s12933-020-01185-3
Zhang, N. (2013) Relationship between ox-LDL and Atherosclerosis and the Anti-Oxidant Effect of Traditional Chinese Medicine. Journal of Yunnan University of Nationalities , 22, 313-316.
Fernández-Friera, L., Fuster, V., López-Melgar, B., Oliva, B., Sánchez-González, J., Macías, A., et al . (2019) Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI. Journal of the American College of Cardiology , 73, 1371-1382. https://doi.org/10.1016/j.jacc.2018.12.075
Wu, C., Tang, Z., Jiang, L., Li, X., Jiang, Z. and Liu, L. (2011) PCSK9 siRNA Inhibits HUVEC Apoptosis Induced by ox-LDL via BCL/Bax-caspase9-caspase3 Pathway. Molecular and Cellular Biochemistry , 359, 347-358. https://doi.org/10.1007/s11010-011-1028-6
Schulz, E., Wenzel, P., Münzel, T. and Daiber, A. (2014) Mitochondrial Redox Signaling: Interaction of Mitochondrial Reactive Oxygen Species with Other Sources of Oxidative Stress. Antioxidants & Redox Signaling , 20, 308-324. https://doi.org/10.1089/ars.2012.4609
Tang, Z., Jiang, L., Peng, J., Ren, Z., Wei, D., Wu, C., et al . (2012) PCSK9 siRNA Suppresses the Inflammatory Response Induced by oxLDL through Inhibition of NF- κ B Activation in Thp-1-Derived Macrophages. International Journal of Molecular Medicine , 30, 931-938. https://doi.org/10.3892/ijmm.2012.1072
Schjerning Olsen, A., Fosbøl, E.L., Lindhardsen, J., Folke, F., Charlot, M., Selmer, C., et al . (2011) Duration of Treatment with Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients with Prior Myocardial Infarction. Circulation , 123, 2226-2235. https://doi.org/10.1161/circulationaha.110.004671
Ding, Z., Pothineni, N.V.K., Goel, A., Lüscher, T.F. and Mehta, J.L. (2019) PCSK9 and Inflammation: Role of Shear Stress, Pro-Inflammatory Cytokines, and Lox-1. Cardiovascular Research , 116, 908-915. https://doi.org/10.1093/cvr/cvz313
Yuan, Y., Wu, W., Sun, S., Zhang, Y. and Chen, Z. (2020) PCSK9: A Potential Therapeutic Target for Sepsis. Journal of Immunology Research , 2020, Article ID: 2687692. https://doi.org/10.1155/2020/2687692
Gurbel, P.A., Jeong, Y., Navarese, E.P. and Tantry, U.S. (2016) Platelet-Mediated Thrombosis. Circulation Research , 118, 1380-1391. https://doi.org/10.1161/circresaha.115.307016
Paciullo, F., Momi, S. and Gresele, P. (2019) PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention. Thrombos is and Haemostasis , 119, 359-367. https://doi.org/10.1055/s-0038-1676863
Hu, Z., Zhang, L. and Yang, J. (2021) Correction to: PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36. Circulation , 143. https://doi.org/10.1161/CIR.0000000000000948
Magwenzi, S., Woodward, C., Wraith, K.S., Aburima, A., Raslan, Z., Jones, H., et al . (2015) Oxidized LDL Activates Blood Platelets through CD36/NOX2-Mediated Inhibition of the cGMP/Protein Kinase G Signaling Cascade. Blood , 125, 2693-2703. https://doi.org/10.1182/blood-2014-05-574491
Cammisotto, V., Baratta, F., Simeone, P.G., Barale, C., Lupia, E., Galardo, G., et al . (2022) Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) beyond Lipids: The Role in Oxidative Stress and Thrombosis. Antioxidants , 11, Article No. 569. https://doi.org/10.3390/antiox11030569
Andrés, V., Pello, O.M. and Silvestre-Roig, C. (2012) Macrophage Proliferation and Apoptosis in Atherosclerosis. Current Opinion in Lipidology , 23, 429-438. https://doi.org/10.1097/mol.0b013e328357a379
Piao, M.-X., Bai, J.-W., Zhang, P.-F. and Zhang, Y.-Z. (2015) PCSK9 Regulates Apoptosis in Human Neuroglioma u251 Cells via Mitochondrial Signaling Pathways. International Journal of Clinical and Experimental Pathology , 8, 2787-2794.
Chistiakov, D.A., Bobryshev, Y.V., Nikiforov, N.G., Elizova, N.V., Sobenin, I.A. and Orekhov, A.N. (2015) RETRACTED: Macrophage Phenotypic Plasticity in Atherosclerosis: The Associated Features and the Peculiarities of the Expression of Inflammatory Genes. International Journal of Cardiology , 184, 436-445. https://doi.org/10.1016/j.ijcard.2015.03.055
Tang, Y., Li, S., Hu, J., Sun, K., Liu, L. and Xu, D. (2020) Research Progress on Alternative Non-Classical Mechanisms of PCSK9 in Atherosclerosis in Patients with and without Diabetes. Cardiovascular Diabetology , 19, Article No. 33. https://doi.org/10.1186/s12933-020-01009-4
Rousselet, E., Marcinkiewicz, J., Kriz, J., Zhou, A., Hatten, M.E., Prat, A., et al . (2011) PCSK9 Reduces the Protein Levels of the LDL Receptor in Mouse Brain during Development and after Ischemic Stroke. Journal of Lipid Research , 52, 1383-1391. https://doi.org/10.1194/jlr.m014118
Seidah, N.G., Awan, Z., Chrétien, M. and Mbikay, M. (2014) PCSK9: A Key Modulator of Cardiovascular Health. Circulation Research , 114, 1022-1036. https://doi.org/10.1161/circresaha.114.301621
Guedeney, P., Giustino, G., Sorrentino, S., Claessen, B.E., Camaj, A., Kalkman, D.N., et al . (2019) Efficacy and Safety of Alirocumab and Evolocumab: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. European Heart Journal , 43, e17-e25. https://doi.org/10.1093/eurheartj/ehz430
Schmidt, A.F., Carter, J.L., Pearce, L.S., Wilkins, J.T., Overington, J.P., Hingorani, A.D., et al . (2020) PCSK9 Monoclonal Antibodies for the Primary and Secondary Prevention of Cardiovascular Disease. Cochrane Database of Systematic Reviews , 2020, CD011748. https://doi.org/10.1002/14651858.cd011748.pub3
Jukema, J.W., Zijlstra, L.E., Bhatt, D.L., Bittner, V.A., Diaz, R., Drexel, H., et al . (2019) Effect of Alirocumab on Stroke in ODYSSEY Outcomes. Circulation , 140, 2054-2062. https://doi.org/10.1161/circulationaha.119.043826
Giugliano, R.P., Pedersen, T.R., Saver, J.L., Sever, P.S., Keech, A.C., Bohula, E.A., et al . (2020) Stroke Prevention with the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients with Stable Atherosclerosis. Stroke , 51, 1546-1554. https://doi.org/10.1161/strokeaha.119.027759
Du, H., Li, X., Su, N., Li, L., Hao, X., Gao, H., et al . (2019) Proprotein Convertase Subtilisin/Kexin 9 Inhibitors in Reducing Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Heart , 105, 1149-1159. https://doi.org/10.1136/heartjnl-2019-314763
Grundy (2023) Correction to: 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation , 148, e5. https://doi.org/10.1161/cir.0000000000001172
Landmesser, U., Chapman, M.J., Stock, J.K., Amarenco, P., Belch, J.J.F., Borén, J., et al . (2017) 2017 Update of ESC/EAS Task Force on Practical Clinical Guidance for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition in Patients with Atherosclerotic Cardiovascular Disease or in Familial Hypercholesterolaemia. European Heart Journal , 39, 1131-1143. https://doi.org/10.1093/eurheartj/ehx549