Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms. Issue 11 (20th October 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Circulation research. Volume 131:Issue 11(2022)
• Page Start: 873
• Page End: 889
• Publication Date: 2022-10-20
• Subjects: graft occlusion, vascular -- inflammation -- macrophage activation -- receptors, LDL -- systems biology; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.320056
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Background: 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.