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Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms
Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973449/ https://www.ncbi.nlm.nih.gov/pubmed/36263780 http://dx.doi.org/10.1161/CIRCRESAHA.121.320056 |
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author | Katsuki, Shunsuke K. Jha, Prabhash Lupieri, Adrien Nakano, Toshiaki Passos, Livia S.A. Rogers, Maximillian A. Becker-Greene, Dakota Le, Thanh-Dat Decano, Julius L. Ho Lee, Lang Guimaraes, Gabriel C. Abdelhamid, Ilyes Halu, Arda Muscoloni, Alessandro V. Cannistraci, Carlo Higashi, Hideyuki Zhang, Hengmin Vromman, Amélie Libby, Peter Keith Ozaki, C. Sharma, Amitabh Singh, Sasha A. Aikawa, Elena Aikawa, Masanori |
author_facet | Katsuki, Shunsuke K. Jha, Prabhash Lupieri, Adrien Nakano, Toshiaki Passos, Livia S.A. Rogers, Maximillian A. Becker-Greene, Dakota Le, Thanh-Dat Decano, Julius L. Ho Lee, Lang Guimaraes, Gabriel C. Abdelhamid, Ilyes Halu, Arda Muscoloni, Alessandro V. Cannistraci, Carlo Higashi, Hideyuki Zhang, Hengmin Vromman, Amélie Libby, Peter Keith Ozaki, C. Sharma, Amitabh Singh, Sasha A. Aikawa, Elena Aikawa, Masanori |
author_sort | Katsuki, Shunsuke |
collection | PubMed |
description | Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. METHODS: We used Ldlr(-/-) mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr(-/-) mouse macrophages. RESULTS: In Ldlr(-/-) mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr(-/-) mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. CONCLUSIONS: Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need. |
format | Online Article Text |
id | pubmed-9973449 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-99734492023-03-01 Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms Katsuki, Shunsuke K. Jha, Prabhash Lupieri, Adrien Nakano, Toshiaki Passos, Livia S.A. Rogers, Maximillian A. Becker-Greene, Dakota Le, Thanh-Dat Decano, Julius L. Ho Lee, Lang Guimaraes, Gabriel C. Abdelhamid, Ilyes Halu, Arda Muscoloni, Alessandro V. Cannistraci, Carlo Higashi, Hideyuki Zhang, Hengmin Vromman, Amélie Libby, Peter Keith Ozaki, C. Sharma, Amitabh Singh, Sasha A. Aikawa, Elena Aikawa, Masanori Circ Res Original Research Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. METHODS: We used Ldlr(-/-) mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr(-/-) mouse macrophages. RESULTS: In Ldlr(-/-) mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr(-/-) mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. CONCLUSIONS: Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need. Lippincott Williams & Wilkins 2022-10-20 2022-11-11 /pmc/articles/PMC9973449/ /pubmed/36263780 http://dx.doi.org/10.1161/CIRCRESAHA.121.320056 Text en © 2022 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Katsuki, Shunsuke K. Jha, Prabhash Lupieri, Adrien Nakano, Toshiaki Passos, Livia S.A. Rogers, Maximillian A. Becker-Greene, Dakota Le, Thanh-Dat Decano, Julius L. Ho Lee, Lang Guimaraes, Gabriel C. Abdelhamid, Ilyes Halu, Arda Muscoloni, Alessandro V. Cannistraci, Carlo Higashi, Hideyuki Zhang, Hengmin Vromman, Amélie Libby, Peter Keith Ozaki, C. Sharma, Amitabh Singh, Sasha A. Aikawa, Elena Aikawa, Masanori Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title | Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title_full | Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title_fullStr | Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title_full_unstemmed | Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title_short | Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms |
title_sort | proprotein convertase subtilisin/kexin 9 (pcsk9) promotes macrophage activation via ldl receptor-independent mechanisms |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973449/ https://www.ncbi.nlm.nih.gov/pubmed/36263780 http://dx.doi.org/10.1161/CIRCRESAHA.121.320056 |
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