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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.
Affiliation
  • Katsuki S; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • K Jha P; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Lupieri A; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Nakano T; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Passos LSA; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Rogers MA; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Becker-Greene D; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Le TD; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Decano JL; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Ho Lee L; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Guimaraes GC; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Abdelhamid I; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Halu A; Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Muscoloni A; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • V Cannistraci C; Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Higashi H; The Biomedical Cybernetics Group, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Center for Systems Biology Dresden, Cluster of Excellence Physics of Life, Department of Physics, Technical University Dresden, Dresden, Germany (A.M., C.V.C).
  • Zhang H; Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.).
  • Vromman A; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Libby P; Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.).
  • Keith Ozaki C; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Sharma A; The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.).
  • Singh SA; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Aikawa E; The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.).
  • Aikawa M; Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.).
Circ Res ; 131(11): 873-889, 2022 11 11.
Article in En | MEDLINE | ID: mdl-36263780
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-1ß (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.
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Full text: 1 Database: MEDLINE Main subject: Proprotein Convertase 9 / Macrophage Activation Type of study: Prognostic_studies Limits: Animals Language: En Journal: Circ Res Year: 2022 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Proprotein Convertase 9 / Macrophage Activation Type of study: Prognostic_studies Limits: Animals Language: En Journal: Circ Res Year: 2022 Type: Article