Evolocumab is a human monoclonal antibody that inhibits protein convertase subtilisin/kexin type 9 (PCSK9) [1]. PCSK9 is a secreted protein that can bind to low-density lipoprotein receptor (LDLR) and transport it to the lysosomal degradation pathway. Evolocumab binds to the circulating PCSK9 protein, which can inhibit its binding to LDLR [2-3]. Evolocumab can be used in the research of hypercholesterolemia and atherosclerotic cardiovascular diseases [4].
In vitro, Evolocumab (0.5–100mg/ml; 24h) pretreatment significantly reduced the cytotoxicity of human umbilical vein endothelial cells (HUVEC) induced by hydrogen peroxide (H2O2), as well as the levels of hydrogen peroxide and MDA, and improved the iron-reducing antioxidant capacity (FRAP) in both intracellular and extracellular culture media [5]. Two hours before hypoxia/reoxygenation (H/R), pretreatment with Evolocumab (100μg/ml) inhibited the decline in AC16 cell viability induced by H/R and successfully reversed the upregulation of LIAS mRNA levels after H/R [6].
In vivo, Evolocumab (10mg/kg/day; twice; s.c.) treatment significantly improved the cardiac injury and functional impairment, inflammation, and oxidative stress in mice with coronary artery disease (I/R) injury, blocked PCSK9, and inhibited the increase in the ratio of infarct area/risk area of I/R [6]. A single-dose treatment with Evolocumab (1, 5, 10mg/kg/day; i.v.) significantly alleviated cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion/reperfusion (MCAO/R) model, upregulated the expression of occludin and claudin-5, and significantly reduced the levels of platelet cells, ICAM-1, VCAM-1, and CD45 [7].
References:
[1] Fala L. Repatha (Evolocumab): Second PCSK9 Inhibitor Approved by the FDA for Patients with Familial Hypercholesterolemia. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):136-9.
[2] Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50 Suppl(Suppl):S172-S177.
[3] Essalmani R, Weider E, Marcinkiewicz J, et al. A single domain antibody against the Cys-and His-rich domain of PCSK9 and evolocumab exhibit different inhibition mechanisms in humanized PCSK9 mice[J]. Biological chemistry, 2018, 399(12): 1363-1374.
[4] Li Z, Zhu H, Liu H, et al. Evolocumab loaded Bio-Liposomes for efficient atherosclerosis therapy[J]. Journal of Nanobiotechnology, 2023, 21(1): 158.
[5] Safaeian L, Mirian M, Bahrizadeh S. Evolocumab, a PCSK9 inhibitor, protects human endothelial cells against H2O2-induced oxidative stress[J]. Archives of physiology and biochemistry, 2022, 128(6): 1681-1686.
[6] Li ZZ, Guo L, An YL, et al. Evolocumab attenuates myocardial ischemia/reperfusion injury by blocking PCSK9/LIAS-mediated cuproptosis of cardiomyocytes. Basic Res Cardiol. 2025;120(2):301-320.
[7] Luo Y, Yuan L, Liu Z, et al. Inhibition of PCSK9 Protects against Cerebral Ischemia‒Reperfusion Injury via Attenuating Microcirculatory Dysfunction. Neurochem Res. 2024;50(1):10.