Abstract 14763: Circulating Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation and Vein Graft Lesion Development in LDL Receptor-Independent Mechanisms.

Background: Vein graft failure is a major clinical problem with no effective medical therapies; however, its underlying mechanisms remain incompletely understood. PCSK9 increases LDL-cholesterol levels by degrading LDL receptor (LDLR) and may promote vascular inflammation. We explored a new mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. Methods and Results: Endotoxin-free recombinant PCSK9 increased the expression of pro-inflammatory molecules (e.g., IL-1β, TNFα, MCP-1) in human primary macrophages and peritoneal macrophages of LDLR-/- mice (Fig. A, n=5), suggesting its LDLR-independent pro-inflammatory effects. We examined in vivo the LDLR-independent role of circulating PCSK9 in experimental vein graft lesions. We transferred the inferior vena cava to the carotid artery of fat-fed LDLR-/- mice and analyzed the grafts 4 weeks after implantation. Hepatic overproduction of PCSK9 involved a single injection of adenoassociated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) or control LacZ (1x1011 vg, i.v.). In LDLR-/- mice, AAV-PCSK9 increased circulating PCSK9, but caused no changes in the serum lipid profile, as expected. By ultrasonography, AAV-PCSK9-treated mice showed statistically significant increases in the vessel wall area and 3D-volume of vein graft lesions than did control mice. These results were consistent with increased intimal area and thickness by AAV-PCSK9 as assessed by histological analysis (Fig. B, n=11-12). Intravital molecular imaging revealed that AAV-PCSK9 promoted macrophage phagocytic and MMP activity associated with decreased collagen. Conclusions: Circulating PCSK9 may induce macrophage activation and contribute to the vein graft lesion development via mechanisms independent of LDLR degradation and blood cholesterol levels. PCSK9 may be a promising therapeutic target for vein graft failure. [ABSTRACT FROM AUTHOR]