PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Goes “DAMP”
2020; Lippincott Williams & Wilkins; Volume: 143; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.120.051940
ISSN1524-4539
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoHomeCirculationVol. 143, No. 1PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Goes "DAMP" Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBPCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Goes "DAMP" Roy L. Silverstein, MD Roy L. SilversteinRoy L. Silverstein Roy L. Silverstein, MD, Linda and John Mellowes Professor and Chair, Department of Medicine, Medical College of Wisconsin, Sr. Investigator and Interim Executive Vice President/Director, Blood Research Institute, Versiti Blood Center of Wisconsin, 8700 W Watertown Plank Rd, Milwaukee, WI 53226. Email E-mail Address: [email protected] Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI. Originally published30 Dec 2020https://doi.org/10.1161/CIRCULATIONAHA.120.051940Circulation. 2021;143:62–64This article is a commentary on the followingPCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36Article, see p 45The story of PCSK9 (proprotein convertase subtilisin/kexin 9) is a triumph of 21st century scientific discovery leading to rapid translation to clinical utility. The story began with genetic discoveries in 2003 showing that gain of function mutations in the PCSK9 gene associated tightly with a rare form of familial hypercholesterolemia,1 and then in 2005 that rare loss of function mutations were associated with very low levels of LDL-C (low-density lipoprotein cholesterol)—30% lower in Black populations and 15% in White populations2—and with an even more impressive reduction in risk of coronary artery disease (CAD)—approximately 90% and 50% respectively.3 Shortly thereafter the cell biology was worked out, revealing that PCSK9 is produced in the liver, secreted, and then binds to the LDLR (LDL receptor), interfering with normal intracellular trafficking and accelerating lysosomal degradation, so that LDLR surface expression is decreased and circulating LDL levels thereby increased.4 The lack of any obvious detrimental effect on health or lifespan in individuals with loss of function mutations and very low LDL-C levels suggested that PCSK9 inhibition could be a viable therapeutic target for CAD. Humanized inhibitory monoclonal antibodies were quickly developed and early phase clinical trials were published in 2012, less than 10 years after the gene discovery, and showed efficacy in lowering LDL-C with no serious adverse side effects. In 2015, the FDA approved the first 2 antibodies, evolocumab and alirocumab, for patients with certain forms of hypercholesterolemia, based on well-designed randomized clinical trials showing improved lipid profiles and CAD outcomes compared to statin therapy alone. These agents, while expensive and cumbersome to deliver, are now part of the standard armimentarium for CAD risk reduction, and clinical research is ongoing to develop effective long-term strategies to inhibit PCSK9, such as with CRISPR/Cas mediated gene therapy.As with all good stories, more complexity was revealed as additional drafts were produced. We learned, for example that PCSK9 regulates expression of many other cellular receptors in addition to LDLR, including metabolic receptors such as the VLDL (very low density lipoprotein) receptor, apoER2 (apolipoprotein E receptor-2), CD36, and LRP-1 (LDL receptor-like protein-1).4 Some of these, including CD36 and LRP-1, are potent signaling receptors expressed on vascular and hematopoietic cells and thus PCSK9 might very well regulate important hemostatic systems, including inflammation, hemostasis, and tissue repair. Observations that PCSK9 inhibitory antibodies offer CAD risk reduction, even in the presence of normal or low LDL-C; and that plasma PCSK9 levels associate with CAD risk independently of LDL-C levels support the hypothesis that some of the beneficial effects of anti-PCSK9 therapy might relate to these other receptor systems.5The elegant study by Qi et al published in this issue of Circulation6 convincingly demonstrates a role for PCSK9 in regulating platelet function through the type 2 scavenger receptor CD36. The authors showed that recombinant PCSK9, when added to washed platelets at concentrations consistent with what are seen in normal human plasma, enhanced platelet activation ex vivo in response to low doses of classical agonists, as assessed by multiple parameters, including aggregation, integrin α2bβ3 activation, granule secretion, and cell spreading. This was reflected in an increase in intravascular thrombosis in vivo in a model of FeCl3-induced arteriolar injury in which the mice were administered recombinant PCSK9 or in which LDLR deficient mice, which are known to have increased PCSK9 plasma levels, were studied.What makes this work truly compelling is the mechanistic studies linking the phenotype to CD36. The investigators used pharmacological, immunologic, and genetic approaches to show that the enhanced platelet responsiveness to classical agonists and the enhanced arterial thrombosis induced by PCSK9 were dependent on platelet CD36 expression and CD36 signaling. PCSK9 addition to platelets activated the CD36 signaling cascade, which has been characterized by our laboratory and others and shown to involve src-family kinases; ERK5, JNK, and P38 MAP kinases; Vav-family guanine nucleotide exchange factors, phospholipase A2; and intracellular reactive oxygen species.7,8 Immunologic blockade of CD36, genetic deletion of CD36, or pharmacological inhibition of CD36 signaling pathways abrogated the effects of PCSK9 in both ex vivo and in vivo studies. Interestingly, the effect of PCSK9 on CD36 activity was not related to suppression of CD36 expression, but rather was due to direct PCSK9 interaction with CD36. In other words. PCSK9 was presumably functioning as a ligand for CD36-mediated platelet activation. The authors showed by coimmunoprecipitation and immuno-fluorescence microscopy that CD36 and PCSK9 likely interacted closely with each other, supporting this hypothesis. Importantly, the apparent binding affinity of PCSK9 for CD36 was within the range of reported circulating PCSK9 plasma concentrations, and was similar to the affinity of known ligands for CD36, such as oxLDL (oxidized LDL).CD36 is very pleiotropic in function,9 serving as a fatty acid transporter on adipocytes and myocytes, a mitochondrial metabolic regulator on macrophages, an anti-angiogenic thrombospondin receptor on microvascular endothelial cells, a proatherosclerotic oxLDL uptake receptor on macrophages, and a proinflammatory signaling receptor on macrophages. The work of Qi et al6 reveals a potentially important connection between PCSK9 and platelet CD36. A role for CD36 as a prothrombotic receptor on platelets is now well established. Podrez et al initially showed that oxLDL interactions with CD36 promoted a platelet-dependent prothrombotic phenotype manifest as enhanced platelet activation to classical agonists10 – similar to what Qi et al6 showed for PCSK9. Human genetic studies have shown strong associations between platelet CD36 surface expression levels with platelet reactivity to oxLDL and with genetic polymorphisms associated with CAD risk,11 and mouse studies have shown that deletion of CD36 or its downstream signaling partners protects animals from high fat diet10 or diabetogenic diet-induced prothrombotic states.12The prothrombotic role of CD36 highlights an important recent recognition that the hemostatic system behaves very differently in settings of chronic inflammatory diseases compared to normal conditions. While studies of platelet function and coagulation enzymes in normal human subjects have yielded enormous insights into human physiology and led to life-saving pharmacological approaches to prevention and treatment of atherothrombosis and venous thrombosis, studies of platelet and coagulation systems in the setting of chronic inflammation, such as cancer, diabetes, hyperlipidemia, atherosclerosis, and obesity have revealed that receptors and enzymes previously not thought to be relevant to normal hemostasis, may in fact be quite relevant to thrombosis. Examples include coagulation factor XII and the contact-activating enzyme system (high molecular weight kininogen and prekalikrein), which are now being studied as contributors to venous thrombosis, especially in the setting of cancer. CD36 also falls into this category as a contributor to arterial thrombosis in the settings of hyperlipidemia, chronic systemic inflammation, and diabetes.The contribution of CD36 to platelet-mediated thrombosis is due to its ability to transmit signals from extracellular cues to the platelet cytoplasm. Relevant CD36 extracellular ligands include oxLDL, advanced glycated proteins,12 S100A family inflammatory peptides,13 and neuropathic amyloid peptides.14 These molecules fall into the general category of "danger associated molecular patterns" or "DAMPs," a broad family of modified endogenous structures generated during inflammation, tissue injury, and oxidant stress that interact with specific scavenger receptors and toll-like receptors to trigger proinflammatory and prothrombotic responses by the innate immune system. Published studies with mouse models show that experimental conditions that mimic type 1 and type 2 diabetes mellitus, obesity, hyperlipidemia, and chronic vascular inflammation generate CD36 ligands in vivo and promote platelet hyper-reactivity and arterial thrombosis. The studies by Qi et al6 strongly support the addition of PCSK9 to the CD36 ligand family, raising the question of whether PCSK9 should be considered a "danger associated molecular pattern" or DAMP, similar to oxLDL, advanced glycated -proteins, S100A, and cell-derived microvesicles. It is interesting to note, PCSK9 expression is enhanced in macrophages by activation of the NLRP3 inflammasome and interleukin-1β15, consistent with this hypothesis.Is there plausibility for high affinity interactions between PCSK9 and CD36? Qi et al6 clearly show physical and functional interactions between the 2 proteins, but direct binding has not yet been proven. Structural studies of PCSK9 binding to LDLR show a critical role for a transient amphipathic helix in the PCSK9 prodomain-4. Since neuropathic amphipathic amyloid peptides are known to bind and activate CD36 in microglial cells,14 it is certainly reasonable to hypothesize that PCSK9 may bind to CD36 via its DAMP-like amphipathic domain.The study by Qi et al6 adds to the growing body of literature supporting an important role for CD36 in promoting platelet hyperactivity and atherothrombosis in disease states and importantly identifies PCSK9 inhibition as a potentially safe therapeutic target to prevent arterial thrombosis in individuals who may be at increased risk because of elevated PCSK9 levels related to genetic or acquired causes, such as inflammation or use of statins.AcknowledgmentsThis work was supported by NIH R01HL142152.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circRoy L. Silverstein, MD, Linda and John Mellowes Professor and Chair, Department of Medicine, Medical College of Wisconsin, Sr. Investigator and Interim Executive Vice President/Director, Blood Research Institute, Versiti Blood Center of Wisconsin, 8700 W Watertown Plank Rd, Milwaukee, WI 53226. Email [email protected]eduReferences1. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, et al.. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat Genet. 2003; 34:154–156. doi: 10.1038/ng1161CrossrefMedlineGoogle Scholar2. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.Nat Genet. 2005; 37:161–165. doi: 10.1038/ng1509CrossrefMedlineGoogle Scholar3. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006; 354:1264–1272. doi: 10.1056/NEJMoa054013CrossrefMedlineGoogle Scholar4. Michael D. Shapiro, Hagai Tavori, Sergio Fazio. PCSK9: from b asic s cience d iscoveries to c linical trials.Circ Res. 2018; 122:1420–1438. doi: 10.1161/CIRCRESAHA.118.311227LinkGoogle Scholar5. Leander K, Mälarstig A, Van't Hooft FM, Hyde C, Hellénius ML, Troutt JS, Konrad RJ, Öhrvik J, Hamsten A, de Faire U. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future r isk of c ardiovascular e vents i ndependently of e stablished r isk f actors.Circulation. 2016; 133:1230–1239. doi: 10.1161/CIRCULATIONAHA.115.018531LinkGoogle Scholar6. Qi Z, Hu L, Zhang J, Yang W, Liu X, Jia D, Yao Z, Chang L, Pan G, Zhong H, et al.. PCSK9 enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36Circulation. 2021; 143:45–61. doi: 10.1161/CIRCULATIONAHA.120.046290LinkGoogle Scholar7. Chen K, Febbraio M, Li W, Silverstein RL. A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein.Circ Res. 2008; 102:1512–1519. doi: 10.1161/CIRCRESAHA.108.172064LinkGoogle Scholar8. Yang M, Silverstein RL. CD36 signaling in vascular redox stress.Free Radic Biol Med. 2019; 136:159–171. doi: 10.1016/j.freeradbiomed.2019.02.021CrossrefMedlineGoogle Scholar9. Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci Signal. 2009; 2:re3. doi: 10.1126/scisignal.272re3CrossrefMedlineGoogle Scholar10. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Valiyaveettil M, Poliakov E, Sun M, Finton PJ, Curtis BR, Chen J, Zhang R, Silverstein RL, Hazen SL. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype.Nat Med. 2007; 13:1086–1095. doi: 10.1038/nm1626CrossrefMedlineGoogle Scholar11. Ghosh A, Murugesan G, Chen K, Zhang L, Wang Q, Febbraio M, Anselmo RM, Marchant K, Barnard J, Silverstein RL. Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms.Blood. 2011; 117:6355–6366. doi: 10.1182/blood-2011-02-338582CrossrefMedlineGoogle Scholar12. Zhu W, Li W, Silverstein RL. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36.Blood. 2012; 119:6136–6144. doi: 10.1182/blood-2011-10-387506CrossrefMedlineGoogle Scholar13. Wang Y, Fang C, Gao H, Bilodeau ML, Zhang Z, Croce K, Liu S, Morooka T, Sakuma M, Nakajima K, Yoneda S, Shi C, Zidar D, Andre P, Stephens G, Silverstein RL, Hogg N, Schmaier AH, Simon DI. Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis.J Clin Invest. 2014; 124:2160–2171. doi: 10.1172/JCI70966CrossrefMedlineGoogle Scholar14. Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.J Neurosci. 2003; 23:2665–2674CrossrefMedlineGoogle Scholar15. Ding Z, Wang X, Liu S, Zhou S, Kore RA, Mu S, Deng X, Fan Y, Mehta JL. NLRP3 inflammasome via IL-1β regulates PCSK9 secretion.Theranostics. 2020; 10:7100–7110. doi: 10.7150/thno.45939CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kong P, Cui Z, Huang X, Zhang D, Guo R and Han M (2022) Inflammation and atherosclerosis: signaling pathways and therapeutic intervention, Signal Transduction and Targeted Therapy, 10.1038/s41392-022-00955-7, 7:1, Online publication date: 1-Dec-2022. Macchi C, Ferri N, Sirtori C, Corsini A, Banach M and Ruscica M (2021) Proprotein Convertase Subtilisin/Kexin Type 9, The American Journal of Pathology, 10.1016/j.ajpath.2021.04.016, 191:8, (1385-1397), Online publication date: 1-Aug-2021. Ortona S, Barisione C, Ferrari P, Palombo D and Pratesi G (2022) PCSK9 and Other Metabolic Targets to Counteract Ischemia/Reperfusion Injury in Acute Myocardial Infarction and Visceral Vascular Surgery, Journal of Clinical Medicine, 10.3390/jcm11133638, 11:13, (3638) Okoro E (2021) TNFα-Induced LDL Cholesterol Accumulation Involve Elevated LDLR Cell Surface Levels and SR-B1 Downregulation in Human Arterial Endothelial Cells, International Journal of Molecular Sciences, 10.3390/ijms22126236, 22:12, (6236) Related articlesPCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36Zhiyong Qi, et al. Circulation. 2021;143:45-61 January 5, 2021Vol 143, Issue 1Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.051940PMID: 33378238 Originally publishedDecember 30, 2020 KeywordsEditorialsplateletsCD36PCSK9thrombosisPDF download Advertisement SubjectsCell Signaling/Signal TransductionMechanismsPathophysiology
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