作者
Shunsuke Katsuki,Prabhash Kumar Jha,Adrien Lupieri,Toshiaki Nakano,Lívia Silva Araújo Passos,Maximillian A. Rogers,Dakota Becker-Greene,Thanh-Dat Le,Julius L. Decano,Lang H Lee,Gabriel C. Guimaraes,Ilyes Abdelhamid,Arda Halu,Alessandro Muscoloni,Carlo Vittorio Cannistraci,Hideyuki Higashi,Hengmin Zhang,Amélie Vromman,Peter Libby,C. Keith Ozaki,Amitabh Sharma,Sasha A Singh,Elena Aikawa,Masanori Aikawa
摘要
BACKGROUND: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. Proprotein convertase subtilisin/kexin 9 (PCSK9) increases 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, TNFα, and MCP-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 signaling molecules, lectin-like oxidized LDL receptor-1, and 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.