PCSK9 Association With Lipoprotein(a).
Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma.



Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B).



We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels.



Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.). fazio@ohsu.edu tavori@ohsu.edu.
Hagai
H
Tavori
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Devon
D
Christian
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Jessica
J
Minnier
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Deanna
D
Plubell
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Michael D
MD
Shapiro
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Calvin
C
Yeang
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Ilaria
I
Giunzioni
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Mikael
M
Croyal
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
P Barton
PB
Duell
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Gilles
G
Lambert
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).
Sotirios
S
Tsimikas
From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.). fazio@ohsu.edu tavori@ohsu.edu.
Sergio
S
Fazio
D000818:Animals; D001054:Apolipoproteins A / Q000097:blood / Q000378:metabolism; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000378:metabolism*; D051379:Mice; D000071449:Proprotein Convertase 9 / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding
D001054:Apolipoproteins A; D001055:Apolipoproteins B; D015415:Biomarkers; D017270:Lipoprotein(a); C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
lipids and lipoprotein metabolism; lipoprotein(a); low-density lipoprotein; proprotein convertase subtilisin/Kexin type 9