Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

PCSK9 and Inflammation: Their Role in Autoimmune Diseases, with a Focus on Rheumatoid Arthritis and Systemic Lupus Erythematosus

Author(s): Stefano Ministrini and Federico Carbone*

Volume 29, Issue 6, 2022

Published on: 04 January, 2022

Page: [970 - 979] Pages: 10

DOI: 10.2174/0929867328666210810150940

Price: $65

Abstract

Despite a clear epidemiological link between autoimmune disease and cardiovascular (CV) risk exists, pathophysiological explanations are extremely complex and far from being elucidated. Dysregulation of metabolic pathways and chronic low-grade inflammation represent common pathways, but CV risk still remains underestimated in patients with autoimmune diseases. Among different candidate mediators, pro-protein convertase subtilisin/kexin type 9 (PCSK9) is attracting growing attention, due to a combined effect on lipid metabolism and inflammatory response. Studies on PCSK9 inhibitors have established a clear benefit on CV outcome without an established effect on inflammation. Conversely, evidence from sepsis and HIV infection strongly supports a pro-inflammatory role of PCSK9. Still, the role of PCSK9 in autoimmune diseases is uncertain. So far, reported clinical findings are controversial and likely reflect the poor knowledge of PCSK9 activity on monocyte/macrophage migration and activation. The complex signaling network around PCSK9 synthesis and metabolism may also have a role, especially concerning the involvement of scavenger receptors, such as CD36. Such complexity in PCSK9 signaling seems particularly evident in autoimmune disease model. This would also potentially explain the observed independency between lipid profile and PCSK9 levels, the so-called “lipid paradox”. In this narrative review, we will summarize the current knowledge about the complex network of PCSK9 signaling. We will focus on upstream and downstream pathways with potential implication in autoimmune disease and potential effects of PCSK9 inhibiting strategies.

Keywords: PCSK9, inflammation, autoimmune disease, rheumatoid arthritis, sepsis, cytokines.

« Previous Next »
[1]
Kawai, V.K.; Shi, M.; Feng, Q.; Chung, C.P.; Liu, G.; Cox, N.J.; Jarvik, G.P.; Lee, M.T.M.; Hebbring, S.J.; Harley, J.B.; Kaufman, K.M.; Namjou, B.; Larson, E.; Gordon, A.S.; Roden, D.M.; Stein, C.M.; Mosley, J.D. Pleiotropy in the genetic predisposition to rheumatoid arthritis: a phenome-wide association study and inverse variance-weighted meta-analysis. Arthritis Rheumatol., 2020, 72(9), 1483-1492.
[http://dx.doi.org/10.1002/art.41291] [PMID: 32307929]
[2]
Carbone, F.; Nencioni, A.; Mach, F.; Vuilleumier, N.; Montecucco, F. Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases. Thromb. Haemost., 2013, 109(5), 854-868.
[http://dx.doi.org/10.1160/TH12-10-0768] [PMID: 23446994]
[3]
Crowson, C.S.; Rollefstad, S.; Ikdahl, E.; Kitas, G.D.; van Riel, P.L.C.M.; Gabriel, S.E.; Matteson, E.L.; Kvien, T.K.; Douglas, K.; Sandoo, A.; Arts, E.; Wållberg-Jonsson, S.; Innala, L.; Karpouzas, G.; Dessein, P.H.; Tsang, L.; El-Gabalawy, H.; Hitchon, C.; Ramos, V.P.; Yáñez, I.C.; Sfikakis, P.P.; Zampeli, E.; Gonzalez-Gay, M.A.; Corrales, A.; Laar, M.V.; Vonkeman, H.E.; Meek, I.; Semb, A.G. Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Ann. Rheum. Dis., 2018, 77(1), 48-54.
[http://dx.doi.org/10.1136/annrheumdis-2017-211735] [PMID: 28877868]
[4]
Leonard, D.; Svenungsson, E.; Dahlqvist, J.; Alexsson, A.; Ärlestig, L.; Taylor, K.E.; Sandling, J.K.; Bengtsson, C.; Frodlund, M.; Jönsen, A.; Eketjäll, S.; Jensen-Urstad, K.; Gunnarsson, I.; Sjöwall, C.; Bengtsson, A.A.; Eloranta, M.L.; Syvänen, A.C.; Rantapää-Dahlqvist, S.; Criswell, L.A.; Rönnblom, L. Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis. Ann. Rheum. Dis., 2018, 77(7), 1063-1069.
[http://dx.doi.org/10.1136/annrheumdis-2017-212614] [PMID: 29514802]
[5]
Carbone, F.; Bonaventura, A.; Liberale, L.; Paolino, S.; Torre, F.; Dallegri, F.; Montecucco, F.; Cutolo, M. Atherosclerosis in rheumatoid arthritis: promoters and opponents. Clin. Rev. Allergy Immunol., 2020, 58(1), 1-14.
[http://dx.doi.org/10.1007/s12016-018-8714-z] [PMID: 30259381]
[6]
Peters, M.J.; Symmons, D.P.; McCarey, D.; Dijkmans, B.A.; Nicola, P.; Kvien, T.K.; McInnes, I.B.; Haentzschel, H.; Gonzalez-Gay, M.A.; Provan, S.; Semb, A.; Sidiropoulos, P.; Kitas, G.; Smulders, Y.M.; Soubrier, M.; Szekanecz, Z.; Sattar, N.; Nurmohamed, M.T. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann. Rheum. Dis., 2010, 69(2), 325-331.
[http://dx.doi.org/10.1136/ard.2009.113696] [PMID: 19773290]
[7]
Aviña-Zubieta, J.A.; To, F.; Vostretsova, K.; De Vera, M.; Sayre, E.C.; Esdaile, J.M. Risk of myocardial infarction and stroke in newly diagnosed systemic lupus erythematosus: a general population-based study. Arthritis Care Res. (Hoboken), 2017, 69(6), 849-856.
[http://dx.doi.org/10.1002/acr.23018] [PMID: 28129475]
[8]
Arkema, E.V.; Svenungsson, E.; Von Euler, M.; Sjöwall, C.; Simard, J.F. Stroke in systemic lupus erythematosus: a Swedish population-based cohort study. Ann. Rheum. Dis., 2017, 76(9), 1544-1549.
[http://dx.doi.org/10.1136/annrheumdis-2016-210973] [PMID: 28400384]
[9]
Li, H.M.; Zhang, T.P.; Leng, R.X.; Li, X.P.; Li, X.M.; Liu, H.R.; Ye, D.Q.; Pan, H.F. Emerging role of adipokines in systemic lupus erythematosus. Immunol. Res., 2016, 64(4), 820-830.
[http://dx.doi.org/10.1007/s12026-016-8808-8] [PMID: 27314594]
[10]
Neumann, E.; Hasseli, R.; Ohl, S.; Lange, U.; Frommer, K.W.; Müller-Ladner, U. Adipokines and Autoimmunity in Inflammatory Arthritis. Cells, 2021, 10(2), 10.
[http://dx.doi.org/10.3390/cells10020216] [PMID: 33499006]
[11]
Díaz, B.B.; González, D.A.; Gannar, F.; Pérez, M.C.R.; de León, A.C. Myokines, physical activity, insulin resistance and autoimmune diseases. Immunol. Lett., 2018, 203, 1-5.
[http://dx.doi.org/10.1016/j.imlet.2018.09.002] [PMID: 30194964]
[12]
An, H.J.; Tizaoui, K.; Terrazzino, S.; Cargnin, S.; Lee, K.H.; Nam, S.W.; Kim, J.S.; Yang, J.W.; Lee, J.Y.; Smith, L.; Koyanagi, A.; Jacob, L.; Li, H.; Shin, J.I.; Kronbichler, A. Sarcopenia in autoimmune and rheumatic diseases: a comprehensive review. Int. J. Mol. Sci., 2020, 21(16), 21.
[http://dx.doi.org/10.3390/ijms21165678] [PMID: 32784808]
[13]
Behl, T.; Kaur, I.; Sehgal, A.; Zengin, G.; Brisc, C.; Brisc, M.C.; Munteanu, M.A.; Nistor-Cseppento, D.C.; Bungau, S. The lipid paradox as a metabolic checkpoint and its therapeutic significance in ameliorating the associated cardiovascular risks in rheumatoid arthritis patients. Int. J. Mol. Sci., 2020, 21(24), 21.
[http://dx.doi.org/10.3390/ijms21249505] [PMID: 33327502]
[14]
Bes, C.; Gürel, S.; Buğdaycı, G.; Dikbaş, O.; Soy, M. Atherosclerosis assessment and rheumatoid arthritis. Z. Rheumatol., 2018, 77(4), 330-334.
[http://dx.doi.org/10.1007/s00393-016-0239-3] [PMID: 27913876]
[15]
Momtazi-Borojeni, A.A.; Sabouri-Rad, S.; Gotto, A.M.; Pirro, M.; Banach, M.; Awan, Z.; Barreto, G.E.; Sahebkar, A. PCSK9 and inflammation: a review of experimental and clinical evidence. Eur. Heart J. Cardiovasc. Pharmacother., 2019, 5(4), 237-245.
[http://dx.doi.org/10.1093/ehjcvp/pvz022] [PMID: 31236571]
[16]
Tang, Z.H.; Peng, J.; Ren, Z.; Yang, J.; Li, T.T.; Li, T.H.; Wang, Z.; Wei, D.H.; Liu, L.S.; Zheng, X.L.; Jiang, Z.S. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis, 2017, 262, 113-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.04.023] [PMID: 28535426]
[17]
Ding, Z.; Pothineni, N.V.K.; Goel, A.; Lüscher, T.F.; Mehta, J.L. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc. Res., 2020, 116(5), 908-915.
[http://dx.doi.org/10.1093/cvr/cvz313] [PMID: 31746997]
[18]
Ding, Z.; Liu, S.; Wang, X.; Deng, X.; Fan, Y.; Shahanawaz, J.; Shmookler Reis, R.J.; Varughese, K.I.; Sawamura, T.; Mehta, J.L. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc. Res., 2015, 107(4), 556-567.
[http://dx.doi.org/10.1093/cvr/cvv178] [PMID: 26092101]
[19]
Ding, Z.; Liu, S.; Wang, X.; Mathur, P.; Dai, Y.; Theus, S.; Deng, X.; Fan, Y.; Mehta, J.L. Cross-talk between PCSK9 and damaged mtDNA in vascular smooth muscle cells: role in apoptosis. Antioxid. Redox Signal., 2016, 25(18), 997-1008.
[http://dx.doi.org/10.1089/ars.2016.6631] [PMID: 27197615]
[20]
Zhang, Y.; Zhu, C.G.; Xu, R.X.; Li, S.; Guo, Y.L.; Sun, J.; Li, J.J. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J. Clin. Lipidol., 2014, 8(5), 494-500.
[http://dx.doi.org/10.1016/j.jacl.2014.07.001] [PMID: 25234562]
[21]
Li, S.; Zhang, Y.; Xu, R.X.; Guo, Y.L.; Zhu, C.G.; Wu, N.Q.; Qing, P.; Liu, G.; Dong, Q.; Li, J.J. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease. Ann. Med., 2015, 47(5), 386-393.
[http://dx.doi.org/10.3109/07853890.2015.1042908] [PMID: 26153823]
[22]
Gencer, B.; Montecucco, F.; Nanchen, D.; Carbone, F.; Klingenberg, R.; Vuilleumier, N.; Aghlmandi, S.; Heg, D.; Räber, L.; Auer, R.; Jüni, P.; Windecker, S.; Lüscher, T.F.; Matter, C.M.; Rodondi, N.; Mach, F. Prognostic value of PCSK9 levels in patients with acute coronary syndromes. Eur. Heart J., 2016, 37(6), 546-553.
[http://dx.doi.org/10.1093/eurheartj/ehv637] [PMID: 26655339]
[23]
Melendez, Q.M.; Krishnaji, S.T.; Wooten, C.J.; Lopez, D. Hypercholesterolemia: The role of PCSK9. Arch. Biochem. Biophys., 2017, 625-626, 39-53.
[http://dx.doi.org/10.1016/j.abb.2017.06.001] [PMID: 28587771]
[24]
Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W.; Davignon, J.; Seidah, N.G.; Prat, A. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology, 2008, 48(2), 646-654.
[http://dx.doi.org/10.1002/hep.22354] [PMID: 18666258]
[25]
Shapiro, M.D.; Fazio, S. PCSK9 and Atherosclerosis - Lipids and Beyond. J. Atheroscler. Thromb., 2017, 24(5), 462-472.
[http://dx.doi.org/10.5551/jat.RV17003] [PMID: 28302950]
[26]
Ferri, N.; Tibolla, G.; Pirillo, A.; Cipollone, F.; Mezzetti, A.; Pacia, S.; Corsini, A.; Catapano, A.L. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis, 2012, 220(2), 381-386.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.11.026] [PMID: 22176652]
[27]
Li, J.J.; Li, S.; Zhang, Y.; Xu, R.X.; Guo, Y.L.; Zhu, C.G.; Wu, N.Q.; Qing, P.; Gao, Y.; Sun, J.; Liu, G.; Dong, Q. Proprotein convertase subtilisin/kexin type 9, c-reactive protein, coronary severity, and outcomes in patients with stable coronary artery disease: a prospective observational cohort study. Medicine (Baltimore), 2015, 94(52), e2426.
[http://dx.doi.org/10.1097/MD.0000000000002426] [PMID: 26717403]
[28]
Acena, A.; Franco Pelaez, J.A.; Pello Lazaro, A.M.; Gonzalez Parra, E.; Gonzalez Lorenzo, O.; Martinez-Milla, J.; Hernandez, I.; Martin-Mariscal, M.L.; Lopez Castillo, M.; Kallmeyer, A.; Lorenzo, O.; Gonzalez-Casaus, M.L.; Egido, J.; Tunon, J. PCSK9 and HS-CRP Predict Progression of Aortic Stenosis in Patients with Stable Coronary Artery Disease. J. Cardiovasc. Transl. Res., 2021, 14(2), 238-245.
[PMID: 32577988]
[29]
Kheirkhah, A.; Lamina, C.; Rantner, B.; Kollerits, B.; Stadler, M.; Pohlhammer, J.; Klein-Weigel, P.; Fraedrich, G.; Kronenberg, F. Elevated levels of serum PCSK9 in male patients with symptomatic peripheral artery disease: The CAVASIC study. Atherosclerosis, 2021, 316, 41-47.
[http://dx.doi.org/10.1016/j.atherosclerosis.2020.11.025] [PMID: 33302043]
[30]
Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; Sever, P.S.; Pedersen, T.R.; Committee, F.S. Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med., 2017, 376, 1713-1722.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[31]
Szarek, M.; White, H.D.; Schwartz, G.G.; Alings, M.; Bhatt, D.L.; Bittner, V.A.; Chiang, C.E.; Diaz, R.; Edelberg, J.M.; Goodman, S.G.; Hanotin, C.; Harrington, R.A.; Jukema, J.W.; Kimura, T.; Kiss, R.G.; Lecorps, G.; Mahaffey, K.W.; Moryusef, A.; Pordy, R.; Roe, M.T.; Tricoci, P.; Xavier, D.; Zeiher, A.M.; Steg, P.G.; Committees, O.O. Alirocumab reduces total nonfatal cardiovascular and fatal events: the odyssey outcomes trial. J. Am. Coll. Cardiol., 2019, 73(4), 387-396.
[http://dx.doi.org/10.1016/j.jacc.2018.10.039] [PMID: 30428396]
[32]
Ruscica, M.; Tokgözoğlu, L.; Corsini, A.; Sirtori, C.R. PCSK9 inhibition and inflammation: A narrative review. Atherosclerosis, 2019, 288, 146-155.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.07.015] [PMID: 31404822]
[33]
Ray, K.K.; Landmesser, U.; Leiter, L.A.; Kallend, D.; Dufour, R.; Karakas, M.; Hall, T.; Troquay, R.P.; Turner, T.; Visseren, F.L.; Wijngaard, P.; Wright, R.S.; Kastelein, J.J. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med., 2017, 376(15), 1430-1440.
[http://dx.doi.org/10.1056/NEJMoa1615758] [PMID: 28306389]
[34]
Rosenson, R.S.; Hegele, R.A.; Fazio, S.; Cannon, C.P. The evolving future of PCSK9 inhibitors. J. Am. Coll. Cardiol., 2018, 72(3), 314-329.
[http://dx.doi.org/10.1016/j.jacc.2018.04.054] [PMID: 30012326]
[35]
Dwivedi, D.J.; Grin, P.M.; Khan, M.; Prat, A.; Zhou, J.; Fox-Robichaud, A.E.; Seidah, N.G.; Liaw, P.C. Differential expression of PCSK9 modulates infection, inflammation, and coagulation in a murine model of sepsis. Shock, 2016, 46(6), 672-680.
[http://dx.doi.org/10.1097/SHK.0000000000000682] [PMID: 27405064]
[36]
Walley, K.R.; Thain, K.R.; Russell, J.A.; Reilly, M.P.; Meyer, N.J.; Ferguson, J.F.; Christie, J.D.; Nakada, T.A.; Fjell, C.D.; Thair, S.A.; Cirstea, M.S.; Boyd, J.H. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci. Transl. Med., 2014, 6(258), 258ra143.
[http://dx.doi.org/10.1126/scitranslmed.3008782] [PMID: 25320235]
[37]
Boyd, J.H.; Fjell, C.D.; Russell, J.A.; Sirounis, D.; Cirstea, M.S.; Walley, K.R. Increased plasma PCSK9 levels are associated with reduced endotoxin clearance and the development of acute organ failures during sepsis. J. Innate Immun., 2016, 8(2), 211-220.
[http://dx.doi.org/10.1159/000442976] [PMID: 26756586]
[38]
Grin, P.M.; Dwivedi, D.J.; Chathely, K.M.; Trigatti, B.L.; Prat, A.; Seidah, N.G.; Liaw, P.C.; Fox-Robichaud, A.E. Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor. Sci. Rep., 2018, 8(1), 10496.
[http://dx.doi.org/10.1038/s41598-018-28777-0] [PMID: 30002483]
[39]
Leung, A.K.K.; Genga, K.R.; Topchiy, E.; Cirstea, M.; Shimada, T.; Fjell, C.; Russell, J.A.; Boyd, J.H.; Walley, K.R. Reduced Proprotein convertase subtilisin/kexin 9 (PCSK9) function increases lipoteichoic acid clearance and improves outcomes in Gram positive septic shock patients. Sci. Rep., 2019, 9(1), 10588.
[http://dx.doi.org/10.1038/s41598-019-46745-0] [PMID: 31332258]
[40]
Topchiy, E.; Cirstea, M.; Kong, H.J.; Boyd, J.H.; Wang, Y.; Russell, J.A.; Walley, K.R. Lipopolysaccharide is cleared from the circulation by hepatocytes via the low density lipoprotein receptor. PLoS One, 2016, 11(5), e0155030.
[http://dx.doi.org/10.1371/journal.pone.0155030] [PMID: 27171436]
[41]
Rannikko, J.; Jacome Sanz, D.; Ortutay, Z.; Seiskari, T.; Aittoniemi, J.; Huttunen, R.; Syrjänen, J.; Pesu, M. Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality. J. Intern. Med., 2019, 286(5), 553-561.
[http://dx.doi.org/10.1111/joim.12946] [PMID: 31166632]
[42]
Vecchié, A.; Bonaventura, A.; Meessen, J.; Novelli, D.; Minetti, S.; Elia, E.; Ferrara, D.; Ansaldo, A.M.; Scaravilli, V.; Villa, S.; Ferla, L.; Caironi, P.; Latini, R.; Carbone, F.; Montecucco, F.; Investigators, A.B.S. PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study. J. Intern. Med., 2021, 289(2), 179-192.
[http://dx.doi.org/10.1111/joim.13150] [PMID: 32686253]
[43]
Innocenti, F.; Gori, A.M.; Giusti, B.; Tozzi, C.; Donnini, C.; Meo, F.; Giacomelli, I.; Ralli, M.L.; Sereni, A.; Sticchi, E.; Tassinari, I.; Marcucci, R.; Pini, R. Plasma PCSK9 levels and sepsis severity: an early assessment in the emergency department. Clin. Exp. Med., 2021, 21(1), 101-107.
[http://dx.doi.org/10.1007/s10238-020-00658-9] [PMID: 32869163]
[44]
Feng, Q.; Wei, W.Q.; Chaugai, S.; Carranza Leon, B.G.; Kawai, V.; Carranza Leon, D.A.; Jiang, L.; Zhong, X.; Liu, G.; Ihegword, A.; Shaffer, C.M.; Linton, M.F.; Chung, C.P.; Stein, C.M. A genetic approach to the association between PCSK9 and sepsis. JAMA Netw. Open, 2019, 2(9), e1911130.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.11130] [PMID: 31509211]
[45]
Mitchell, K.A.; Moore, J.X.; Rosenson, R.S.; Irvin, R.; Guirgis, F.W.; Shapiro, N.; Safford, M.; Wang, H.E. PCSK9 loss-of-function variants and risk of infection and sepsis in the reasons for geographic and racial differences in stroke (REGARDS) cohort. PLoS One, 2019, 14(2), e0210808.
[http://dx.doi.org/10.1371/journal.pone.0210808] [PMID: 30726226]
[46]
Boccara, F.; Ghislain, M.; Meyer, L.; Goujard, C.; Le May, C.; Vigouroux, C.; Bastard, J.P.; Fellahi, S.; Capeau, J.; Cohen, A.; Cariou, B. Impact of protease inhibitors on circulating PCSK9 levels in HIV-infected antiretroviral-naive patients from an ongoing prospective cohort. AIDS, 2017, 31(17), 2367-2376.
[http://dx.doi.org/10.1097/QAD.0000000000001633] [PMID: 28857822]
[47]
Bianconi, V.; Schiaroli, E.; Pirro, M.; Cardaci, S.; Busti, C.; Mannarino, M.R.; Baldelli, F.; Francisci, D. Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: focus on lipids, inflammation and immunovirological parameters. HIV Med., 2020, 21(8), 512-522.
[http://dx.doi.org/10.1111/hiv.12884] [PMID: 32496664]
[48]
Gencer, B.; Pagano, S.; Vuilleumier, N.; Satta, N.; Delhumeau-Cartier, C.; Meier, C.; Bavamian, S.; Montecucco, F.; Mach, F.; Calmy, A. Clinical, behavioral and biomarker predictors of PCSK9 levels in HIV-infected patients naïve of statin therapy: A cross-sectional analysis from the Swiss HIV cohort. Atherosclerosis, 2019, 284, 253-259.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.02.015] [PMID: 30827714]
[49]
Zanni, M.V.; Stone, L.A.; Toribio, M.; Rimmelin, D.E.; Robinson, J.; Burdo, T.H.; Williams, K.; Fitch, K.V.; Lo, J.; Grinspoon, S.K. Proprotein convertase subtilisin/kexin 9 levels in relation to systemic immune activation and subclinical coronary plaque in HIV. Open Forum Infect. Dis., 2017, 4(4), ofx227.
[http://dx.doi.org/10.1093/ofid/ofx227] [PMID: 29226174]
[50]
Leucker, T.M.; Weiss, R.G.; Schär, M.; Bonanno, G.; Mathews, L.; Jones, S.R.; Brown, T.T.; Moore, R.; Afework, Y.; Gerstenblith, G.; Hays, A.G. Coronary endothelial dysfunction is associated with elevated serum PCSK9 levels in people with HIV independent of low-density lipoprotein cholesterol. J. Am. Heart Assoc., 2018, 7(19), e009996.
[http://dx.doi.org/10.1161/JAHA.118.009996] [PMID: 30371326]
[51]
Ferraz-Amaro, I.; López-Mejías, R.; Ubilla, B.; Genre, F.; Tejera-Segura, B.; de Vera-González, A.M.; González-Rivero, A.F.; Olmos, J.M.; Hernández, J.L.; Llorca, J.; González-Gay, M.A. Proprotein convertase subtilisin/kexin type 9 in rheumatoid arthritis. Clin. Exp. Rheumatol., 2016, 34(6), 1013-1019.
[PMID: 27606890]
[52]
Ferraz-Amaro, I.; Hernández-Hernández, M.V.; Tejera-Segura, B.; Delgado-Frías, E.; Macía-Díaz, M.; Machado, J.D.; Diaz-González, F. Effect of IL-6 receptor blockade on proprotein convertase subtilisin/kexin type-9 and cholesterol efflux capacity in rheumatoid arthritis patients. Horm. Metab. Res., 2019, 51(3), 200-209.
[http://dx.doi.org/10.1055/a-0833-4627] [PMID: 30695794]
[53]
Frostegård, J.; Ahmed, S.; Hafström, I.; Ajeganova, S.; Rahman, M. Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms. Arthritis Res. Ther., 2021, 23(1), 32.
[http://dx.doi.org/10.1186/s13075-020-02386-7] [PMID: 33461620]
[54]
Ferraz-Amaro, I.; Delgado-Frías, E.; Hernández-Hernández, V.; Sánchez-Pérez, H.; de Armas-Rillo, L.; García-Dopico, J.A.; Díaz-González, F. Proprotein convertase subtilisin/kexin type 9 in patients with systemic sclerosis. Clin. Exp. Rheumatol., 2020, 38(3)(Suppl. 125), 18-24.
[PMID: 32324120]
[55]
Fang, C.; Luo, T.; Lin, L. Elevation of serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations and its possible atherogenic role in patients with systemic lupus erythematosus. Ann. Transl. Med., 2018, 6(23), 452.
[http://dx.doi.org/10.21037/atm.2018.11.04] [PMID: 30603640]
[56]
Liu, A.; Rahman, M.; Hafström, I.; Ajeganova, S.; Frostegård, J. Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus. Lupus, 2020, 29(8), 825-835.
[http://dx.doi.org/10.1177/0961203320926253] [PMID: 32479241]
[57]
Sanchez-Perez, H; Quevedo-Abeledo, JC; Tejera-Segura, B; de Armas-Rillo, L; Rua-Figueroa, I; Gonzalez-Gay, MA; Ferraz-Amaro, I Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus. Ther Adv Musculoskelet Dis, 2020, 12, 1759720X20975904.
[http://dx.doi.org/10.1177/1759720X20975904] [PMID: 33294038]
[58]
Tang, Z.H.; Li, T.H.; Peng, J.; Zheng, J.; Li, T.T.; Liu, L.S.; Jiang, Z.S.; Zheng, X.L. PCSK9: A novel inflammation modulator in atherosclerosis? J. Cell. Physiol., 2019, 234(3), 2345-2355.
[http://dx.doi.org/10.1002/jcp.27254] [PMID: 30246446]
[59]
Sun, L.; Yang, X.; Li, Q.; Zeng, P.; Liu, Y.; Liu, L.; Chen, Y.; Yu, M.; Ma, C.; Li, X.; Li, Y.; Zhang, R.; Zhu, Y.; Miao, Q.R.; Han, J.; Duan, Y. Activation of adiponectin receptor regulates proprotein convertase subtilisin/kexin type 9 expression and inhibits lesions in apoe-deficient mice. Arterioscler. Thromb. Vasc. Biol., 2017, 37(7), 1290-1300.
[http://dx.doi.org/10.1161/ATVBAHA.117.309630] [PMID: 28546220]
[60]
Seleit, I.; Bakry, O.A.; Abd El Gayed, E.; Ghanem, M. Peroxisome proliferator-activated receptor-γ gene polymorphism in psoriasis and its relation to obesity, metabolic syndrome, and narrowband ultraviolet B response: a case-control study in egyptian patients. Indian J. Dermatol., 2019, 64(3), 192-200.
[http://dx.doi.org/10.4103/ijd.IJD_114_18] [PMID: 31148857]
[61]
Laugier-Robiolle, S.; Vergès, B.; Le Bras, M.; Gand, E.; Bouillet, B.; Saulnier, P.J.; Le May, C.; Pichelin, M.; Maréchaud, R.; Petit, J.M.; Hadjadj, S.; Cariou, B. Glycaemic control influences the relationship between plasma PCSK9 and LDL cholesterol in type 1 diabetes. Diabetes Obes. Metab., 2017, 19(3), 448-451.
[http://dx.doi.org/10.1111/dom.12819] [PMID: 27804190]
[62]
Levenson, A.E.; Wadwa, R.P.; Shah, A.S.; Khoury, P.R.; Kimball, T.R.; Urbina, E.M.; de Ferranti, S.D.; Bishop, F.K.; Maahs, D.M.; Dolan, L.M.; Biddinger, S.B. PCSK9 is increased in youth with type 1 diabetes. Diabetes Care, 2017, 40(7), e85-e87.
[http://dx.doi.org/10.2337/dc16-2563] [PMID: 28588146]
[63]
Lotta, L.A.; Sharp, S.J.; Burgess, S.; Perry, J.R.B.; Stewart, I.D.; Willems, S.M.; Luan, J.; Ardanaz, E.; Arriola, L.; Balkau, B.; Boeing, H.; Deloukas, P.; Forouhi, N.G.; Franks, P.W.; Grioni, S.; Kaaks, R.; Key, T.J.; Navarro, C.; Nilsson, P.M.; Overvad, K.; Palli, D.; Panico, S.; Quirós, J.R.; Riboli, E.; Rolandsson, O.; Sacerdote, C.; Salamanca, E.C.; Slimani, N.; Spijkerman, A.M.; Tjonneland, A.; Tumino, R. van der A, D.L.; van der Schouw, Y.T.; McCarthy, M.I.; Barroso, I.; O’Rahilly, S.; Savage, D.B.; Sattar, N.; Langenberg, C.; Scott, R.A.; Wareham, N.J. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA, 2016, 316(13), 1383-1391.
[http://dx.doi.org/10.1001/jama.2016.14568] [PMID: 27701660]
[64]
Schmidt, A.F.; Swerdlow, D.I.; Holmes, M.V.; Patel, R.S.; Fairhurst-Hunter, Z.; Lyall, D.M.; Hartwig, F.P.; Horta, B.L.; Hyppönen, E.; Power, C.; Moldovan, M.; van Iperen, E.; Hovingh, G.K.; Demuth, I.; Norman, K.; Steinhagen-Thiessen, E.; Demuth, J.; Bertram, L.; Liu, T.; Coassin, S.; Willeit, J.; Kiechl, S.; Willeit, K.; Mason, D.; Wright, J.; Morris, R.; Wanamethee, G.; Whincup, P.; Ben-Shlomo, Y.; McLachlan, S.; Price, J.F.; Kivimaki, M.; Welch, C.; Sanchez-Galvez, A.; Marques-Vidal, P.; Nicolaides, A.; Panayiotou, A.G.; Onland-Moret, N.C.; van der Schouw, Y.T.; Matullo, G.; Fiorito, G.; Guarrera, S.; Sacerdote, C.; Wareham, N.J.; Langenberg, C.; Scott, R.; Luan, J.; Bobak, M.; Malyutina, S.; Pająk, A.; Kubinova, R.; Tamosiunas, A.; Pikhart, H.; Husemoen, L.L.; Grarup, N.; Pedersen, O.; Hansen, T.; Linneberg, A.; Simonsen, K.S.; Cooper, J.; Humphries, S.E.; Brilliant, M.; Kitchner, T.; Hakonarson, H.; Carrell, D.S.; McCarty, C.A.; Kirchner, H.L.; Larson, E.B.; Crosslin, D.R.; de Andrade, M.; Roden, D.M.; Denny, J.C.; Carty, C.; Hancock, S.; Attia, J.; Holliday, E.; O’Donnell, M.; Yusuf, S.; Chong, M.; Pare, G.; van der Harst, P.; Said, M.A.; Eppinga, R.N.; Verweij, N.; Snieder, H.; Christen, T.; Mook-Kanamori, D.O.; Gustafsson, S.; Lind, L.; Ingelsson, E.; Pazoki, R.; Franco, O.; Hofman, A.; Uitterlinden, A.; Dehghan, A.; Teumer, A.; Baumeister, S.; Dörr, M.; Lerch, M.M.; Völker, U.; Völzke, H.; Ward, J.; Pell, J.P.; Smith, D.J.; Meade, T.; Maitland-van der Zee, A.H.; Baranova, E.V.; Young, R.; Ford, I.; Campbell, A.; Padmanabhan, S.; Bots, M.L.; Grobbee, D.E.; Froguel, P.; Thuillier, D.; Balkau, B.; Bonnefond, A.; Cariou, B.; Smart, M.; Bao, Y.; Kumari, M.; Mahajan, A.; Ridker, P.M.; Chasman, D.I.; Reiner, A.P.; Lange, L.A.; Ritchie, M.D.; Asselbergs, F.W.; Casas, J.P.; Keating, B.J.; Preiss, D.; Hingorani, A.D.; Sattar, N. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol., 2017, 5(2), 97-105.
[http://dx.doi.org/10.1016/S2213-8587(16)30396-5] [PMID: 27908689]
[65]
Grune, J.; Meyborg, H.; Bezhaeva, T.; Kappert, K.; Hillmeister, P.; Kintscher, U.; Pieske, B.; Stawowy, P. PCSK9 regulates the chemokine receptor CCR2 on monocytes. Biochem. Biophys. Res. Commun., 2017, 485(2), 312-318.
[http://dx.doi.org/10.1016/j.bbrc.2017.02.085] [PMID: 28232185]
[66]
Bernelot Moens, S.J.; Neele, A.E.; Kroon, J.; van der Valk, F.M.; Van den Bossche, J.; Hoeksema, M.A.; Hoogeveen, R.M.; Schnitzler, J.G.; Baccara-Dinet, M.T.; Manvelian, G.; de Winther, M.P.J.; Stroes, E.S.G. PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia. Eur. Heart J., 2017, 38(20), 1584-1593.
[http://dx.doi.org/10.1093/eurheartj/ehx002] [PMID: 28329114]
[67]
Demers, A.; Samami, S.; Lauzier, B.; Des Rosiers, C.; Ngo Sock, E.T.; Ong, H.; Mayer, G. PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler. Thromb. Vasc. Biol., 2015, 35(12), 2517-2525.
[http://dx.doi.org/10.1161/ATVBAHA.115.306032] [PMID: 26494228]
[68]
Qi, Z.; Hu, L.; Zhang, J.; Yang, W.; Liu, X.; Jia, D.; Yao, Z.; Chang, L.; Pan, G.; Zhong, H.; Luo, X.; Yao, K.; Sun, A.; Qian, J.; Ding, Z.; Ge, J. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation, 2021, 143(1), 45-61.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046290] [PMID: 32988222]
[69]
Voloshyna, I.; Modayil, S.; Littlefield, M.J.; Belilos, E.; Belostocki, K.; Bonetti, L.; Rosenblum, G.; Carsons, S.E.; Reiss, A.B. Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages. Exp. Biol. Med. (Maywood), 2013, 238(10), 1192-1197.
[http://dx.doi.org/10.1177/1535370213503262] [PMID: 24000379]
[70]
Krabben, A.; Huizinga, T.W.; Mil, A.H. Biomarkers for radiographic progression in rheumatoid arthritis. Curr. Pharm. Des., 2015, 21(2), 147-169.
[http://dx.doi.org/10.2174/1381612820666140825122525] [PMID: 25163742]
[71]
Dixon, W.G.; Watson, K.D.; Lunt, M.; Hyrich, K.L.; Silman, A.J.; Symmons, D.P. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum., 2007, 56(9), 2905-2912.
[http://dx.doi.org/10.1002/art.22809] [PMID: 17763428]
[72]
Choy, E.; Sattar, N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann. Rheum. Dis., 2009, 68(4), 460-469.
[http://dx.doi.org/10.1136/ard.2008.101964] [PMID: 19286905]
[73]
Wiciński, M.; Żak, J.; Malinowski, B.; Popek, G.; Grześk, G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J., 2017, 8(4), 391-402.
[http://dx.doi.org/10.1007/s13167-017-0106-6] [PMID: 29209441]
[74]
Sabatine, M.S.; Leiter, L.A.; Wiviott, S.D.; Giugliano, R.P.; Deedwania, P.; De Ferrari, G.M.; Murphy, S.A.; Kuder, J.F.; Gouni-Berthold, I.; Lewis, B.S.; Handelsman, Y.; Pineda, A.L.; Honarpour, N.; Keech, A.C.; Sever, P.S.; Pedersen, T.R. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol., 2017, 5(12), 941-950.
[http://dx.doi.org/10.1016/S2213-8587(17)30313-3] [PMID: 28927706]
[75]
Leiter, L.A.; Teoh, H.; Kallend, D.; Wright, R.S.; Landmesser, U.; Wijngaard, P.L.J.; Kastelein, J.J.P.; Ray, K.K. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care, 2019, 42(1), 173-176.
[http://dx.doi.org/10.2337/dc18-1491] [PMID: 30487231]
[76]
Ray, K.K.; Del Prato, S.; Müller-Wieland, D.; Cariou, B.; Colhoun, H.M.; Tinahones, F.J.; Domenger, C.; Letierce, A.; Mandel, J.; Samuel, R.; Bujas-Bobanovic, M.; Leiter, L.A. Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies. Cardiovasc. Diabetol., 2019, 18(1), 149.
[http://dx.doi.org/10.1186/s12933-019-0951-9] [PMID: 31706300]
[77]
Targeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids. Available from: . https://ClinicalTrials.gov/show/NCT04485871
[78]
Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes. Available from: . https://ClinicalTrials.gov/show/NCT03344692
[79]
The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease. Available from: . https://ClinicalTrials.gov/show/NCT03829046
[80]
Expanded Combination of Evolocumab Plus Empagliflozin on Diabetes. Available from: . https://ClinicalTrials.gov/show/NCT03932721
[81]
Cholesterol Lowering and Residual Risk in Type 2 Diabetes. Available from: . https://ClinicalTrials.gov/show/NCT043-69664
[82]
Khademi, F.; Momtazi-Borojeni, A.A.; Reiner, Ž.; Banach, M.; Al-Rasadi, K.A.; Sahebkar, A. PCSK9 and infection: A potentially useful or dangerous association? J. Cell. Physiol., 2018, 233(4), 2920-2927.
[http://dx.doi.org/10.1002/jcp.26040] [PMID: 28574577]

Rights & Permissions Print Cite
Article Metrics
70
1
World Chagas Disease
© 2024 Bentham Science Publishers | Privacy Policy