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Research Article

PCSK9肽疫苗在小鼠体内的免疫潜力

卷 30, 期 26, 2023

发表于: 08 December, 2022

页: [3024 - 3031] 页: 8

弟呕挨: 10.2174/0929867329666220930114429

价格: $65

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摘要

目的：评估基于无载体肽的抗 PCSK9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9）疫苗在白化小鼠中的免疫原性潜力。 方法：将免疫原性 pcsk9 肽和 0.4% 明矾佐剂以 1:1 的比例充分混合，用作疫苗制剂。为了评估体液免疫反应，在最后一次免疫两周后对动物的血液进行了采样。采用 ELISA 方法测量血清抗 PCSK9 抗体滴度、PCSK9 浓度和 PCSK9/LDLR 相互作用。 结果：ELISA 分析显示，与对照小鼠相比，接种小鼠血清中 PCSK9 肽疫苗可显着诱导 IgG 抗体滴度（雄性和雌性小鼠分别为 12000±586 和 11566±642，p<0.001）。机制分析表明，与对照组相比，疫苗组中疫苗诱导的抗体可显着降低血清 PCSK9 浓度（雄性小鼠降低 29±5 ng/mL (22.4%)，p<0.001，雌性小鼠降低 26±5 ng / mL (21.0%)，p<0.001）。对照组和疫苗组的 PCSK9 血清浓度在雄性小鼠中分别为 131±8.6 ng/mL 和 102±8.1 ng/ml，在雌性小鼠中分别为 124±6 ng/ml 和 98±10 ng/ml。此外，疫苗诱导的抗体在男性和女性组中分别抑制了 34% 和 26% 的 PCSK9-LDLR 相互作用。在所有测试中，男性和女性组之间没有检测到显着差异（p>0.05）。 结论：根据我们的结果，PCSK9 肽疫苗可激发白化小鼠的体液免疫系统产生抑制血浆 PCSK9 的功能性抗体。这些影响在两种性别中都可以看到，没有任何显着差异。

关键词: PCSK9，低密度脂蛋白胆固醇，肽疫苗，免疫原性潜能，抗PCSK9，酶联免疫吸附法。

« Previous Next »
[1]
Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M. Heart disease and stroke statistics-2015 update: A report from the American Heart Association. Circulation, 2015, 131(4), e29-e322.
[2]
Yusuf, S.; Hawken, S.; Ôunpuu, S.; Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.; Varigos, J.; Lisheng, L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet, 2004, 364(9438), 937-952.
[http://dx.doi.org/10.1016/S0140-6736(04)17018-9] [PMID: 15364185]
[3]
Vallejo-Vaz, A.J.; De Marco, M.; Stevens, C.A.T.; Akram, A.; Freiberger, T.; Hovingh, G.K.; Kastelein, J.J.P.; Mata, P.; Raal, F.J.; Santos, R.D.; Soran, H.; Watts, G.F.; Abifadel, M.; Aguilar-Salinas, C.A.; Al-Khnifsawi, M.; AlKindi, F.A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Al-Sarraf, A.; Ashavaid, T.F.; Binder, C.J.; Bogsrud, M.P.; Bourbon, M.; Bruckert, E.; Chlebus, K.; Corral, P.; Descamps, O.; Durst, R.; Ezhov, M.; Fras, Z.; Genest, J.; Groselj, U.; Harada-Shiba, M.; Kayikcioglu, M.; Lalic, K.; Lam, C.S.P.; Latkovskis, G; Laufs, U.; Liberopoulos, E.; Lin, J.; Maher, V.; Majano, N.; Marais, A.D.; März, W.; Mirrakhimov, E.; Miserez, A.R.; Mitchenko, O.; Nawawi, H.M.; Nordestgaard, B.G.; Paragh, G.; Petrulioniene, Z.; Pojskic, B.; Postadzhiyan, A.; Reda, A.; Reiner, Ž.; Sadoh, W.E.; Sahebkar, A.; Shehab, A.; Shek, A.B.; Stoll, M.; Su, T.C.; Subramaniam, T.; Susekov, A.V.; Symeonides, P.; Tilney, M.; Tomlinson, B.; Truong, T.H.; Tselepis, A.D.; Tybjærg-Hansen, A.; Vázquez-Cárdenas, A.; Viigimaa, M.; Vohnout, B.; Widén, E.; Yamashita, S.; Banach, M.; Gaita, D.; Jiang, L.; Nilsson, L.; Santos, L.E.; Schunkert, H.; Tokgözoğlu, L.; Car, J.; Catapano, A.L; Ray, K.K EAS Familial Hypercholesterolaemia Studies Collaboration. EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) Investigators. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis, 2018, 277, 234-255.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.051] [PMID: 30270054]
[4]
Brown, M.S.; Goldstein, J.L. A receptor-mediated pathway for cholesterol homeostasis. Science, 1986, 232(4746), 34-47.
[http://dx.doi.org/10.1126/science.3513311] [PMID: 3513311]
[5]
Malo, J.; Parajuli, A.; Walker, S.W. PCSK9: From molecular biology to clinical applications. Ann. Clin. Biochem., 2020, 57(1), 7-25.
[http://dx.doi.org/10.1177/0004563219864379] [PMID: 31257903]
[6]
Glerup, S.; Schulz, R.; Laufs, U.; Schlüter, K.D. Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res. Cardiol., 2017, 112(3), 32.
[http://dx.doi.org/10.1007/s00395-017-0619-0] [PMID: 28439730]
[7]
Seidah, N.G. The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer. J. Lipid Res., 2021, 62, 100130.
[http://dx.doi.org/10.1016/j.jlr.2021.100130] [PMID: 34606887]
[8]
Catapano, A.L.; Papadopoulos, N. The safety of therapeutic monoclonal antibodies: Implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis, 2013, 228(1), 18-28.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.044] [PMID: 23466067]
[9]
Sahebkar, A.; Momtazi-Borojeni, A.A.; Banach, M. PCSK9 vaccine: So near, yet so far! Eur. Heart J., 2021, 42(39), 4007-4010.
[http://dx.doi.org/10.1093/eurheartj/ehab299] [PMID: 34151957]
[10]
Momtazi-Borojeni, A.A.; Pirro, M.; Xu, S.; Sahebkar, A. PCSK9 inhibition-based therapeutic approaches: An immunotherapy perspective. Curr. Med. Chem., 2022, 29(6), 980-999.
[http://dx.doi.org/10.2174/0929867328666211027125245] [PMID: 34711156]
[11]
Sahebkar, A.; Watts, G.F. New LDL-cholesterol lowering therapies: Pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin. Ther., 2013, 35(8), 1082-1098.
[http://dx.doi.org/10.1016/j.clinthera.2013.06.019] [PMID: 23932550]
[12]
Zambon, A.; Averna, M.; D’Erasmo, L.; Arca, M.; Catapano, A. New and emerging therapies for dyslipidemia. Endocrinol. Metab. Clin. North Am., 2022, 51(3), 635-653.
[http://dx.doi.org/10.1016/j.ecl.2022.02.004] [PMID: 35963633]
[13]
Do, R.Q.; Vogel, R.A.; Schwartz, G.G. PCSK9 inhibitors: Potential in cardiovascular therapeutics. Curr. Cardiol. Rep., 2013, 15(3), 345.
[http://dx.doi.org/10.1007/s11886-012-0345-z] [PMID: 23338726]
[14]
Sahebkar, A.; Watts, G.F. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: What can the clinician expect? Cardiovasc. Drugs Ther., 2013, 27(6), 559-567.
[http://dx.doi.org/10.1007/s10557-013-6479-4] [PMID: 23913122]
[15]
Galabova, G.; Brunner, S.; Winsauer, G.; Juno, C.; Wanko, B.; Mairhofer, A.; Lührs, P.; Schneeberger, A.; von Bonin, A.; Mattner, F.; Schmidt, W.; Staffler, G. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One, 2014, 9(12), e114469.
[http://dx.doi.org/10.1371/journal.pone.0114469] [PMID: 25474576]
[16]
Fattori, E.; Cappelletti, M.; Lo Surdo, P.; Calzetta, A.; Bendtsen, C.; Ni, Y.G.; Pandit, S.; Sitlani, A.; Mesiti, G.; Carfí, A.; Monaci, P. Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice. J. Lipid Res., 2012, 53(8), 1654-1661.
[http://dx.doi.org/10.1194/jlr.M028340] [PMID: 22611251]
[17]
Crossey, E.; Amar, M.J.A.; Sampson, M.; Peabody, J.; Schiller, J.T.; Chackerian, B.; Remaley, A.T. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine, 2015, 33(43), 5747-5755.
[http://dx.doi.org/10.1016/j.vaccine.2015.09.044] [PMID: 26413878]
[18]
Chyu, K.Y.; Shah, P.K. In pursuit of an atherosclerosis vaccine: Chasing the Holy Grail. Circ. Res., 2018, 123(10), 1121-1123.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313842] [PMID: 30359192]
[19]
Pulendran, B.; S Arunachalam, P.; O’Hagan, D.T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov., 2021, 20(6), 454-475.
[http://dx.doi.org/10.1038/s41573-021-00163-y] [PMID: 33824489]
[20]
Bachmann, M.F.; Dyer, M.R. Therapeutic vaccination for chronic diseases: A new class of drugs in sight. Nat. Rev. Drug Discov., 2004, 3(1), 81-88.
[http://dx.doi.org/10.1038/nrd1284] [PMID: 14666113]
[21]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Badiee, A.; Sahebkar, A. Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system. Atherosclerosis, 2019, 283, 69-78.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.02.001] [PMID: 30797988]
[22]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Badiee, A.; Banach, M.; Sahebkar, A. Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med., 2019, 17(1), 223.
[http://dx.doi.org/10.1186/s12916-019-1457-8] [PMID: 31818299]
[23]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Afshar, M.; Banach, M.; Sahebkar, A. PCSK9 immunization using nanoliposomes: Preventive efficacy against hypercholesterolemia and atherosclerosis. Arch. Med. Sci., 2021, 17(5), 1365-1377.
[http://dx.doi.org/10.5114/aoms/133885] [PMID: 34522266]
[24]
Schneeberger, A.; Mandler, M.; Otava, O.; Zauner, W.; Mattner, F.; Schmidt, W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD): From concept to clinical testing. J. Nutr. Health Aging, 2009, 13(3), 264-267.
[http://dx.doi.org/10.1007/s12603-009-0070-5] [PMID: 19262965]
[25]
Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.A.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.G.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur. Heart J., 2017, 38(32), 2499-2507.
[http://dx.doi.org/10.1093/eurheartj/ehx260] [PMID: 28637178]
[26]
Kawakami, R.; Nozato, Y.; Nakagami, H.; Ikeda, Y.; Shimamura, M.; Yoshida, S.; Sun, J.; Kawano, T.; Takami, Y.; Noma, T.; Rakugi, H.; Minamino, T.; Morishita, R. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS One, 2018, 13(2), e0191895.
[http://dx.doi.org/10.1371/journal.pone.0191895] [PMID: 29438441]
[27]
Momtazi-Borojeni, A.A.; Ebrahimi Nik, M.; Reza Jaafari, M.; Banach, M.; Sahebkar, A. Effects of immunisation against PCSK9 in mice bearing melanoma. Arch. Med. Sci., 2020, 16(1), 189-199.
[http://dx.doi.org/10.5114/aoms.2020.91291] [PMID: 32051723]
[28]
Momtazi-Borojeni, A.A.; Jaafari, M.R.; Abdollahi, E.; Banach, M.; Sahebkar, A. Impact of PCSK9 immunization on glycemic indices in diabetic rats. J. Diabetes Res., 2021, 2021
[http://dx.doi.org/10.1155/2021/4757170]
[29]
Pan, Y.; Zhou, Y.; Wu, H.; Chen, X.; Hu, X.; Zhang, H.; Zhou, Z.; Qiu, Z.; Liao, Y. A therapeutic peptide vaccine against PCSK9. Sci. Rep., 2017, 7(1), 12534.
[http://dx.doi.org/10.1038/s41598-017-13069-w] [PMID: 28970592]
[30]
Wu, D.; Pan, Y.; Yang, S.; Li, C.; Zhou, Y.; Wang, Y.; Chen, X.; Zhou, Z.; Liao, Y.; Qiu, Z. PCSK9Qβ-003 vaccine attenuates atherosclerosis in Apolipoprotein E-deficient mice. Cardiovasc. Drugs Ther., 2021, 35(1), 141-151.
[http://dx.doi.org/10.1007/s10557-020-07041-6] [PMID: 32725442]
[31]
You, S.; Guo, X.; Xue, X.; Li, Y.; Dong, H.; Ji, H.; Hong, T.; Wei, Y.; Shi, X.; He, B. PCSK9 hapten multicopy displayed onto carrier protein nanoparticle: An antiatherosclerosis vaccine. ACS Biomater. Sci. Eng., 2019, 5(9), 4263-4271.
[http://dx.doi.org/10.1021/acsbiomaterials.9b00434] [PMID: 33417782]

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