PCSK9 Association With Lipoprotein(a)

Abstract

Rationale Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein (LDL)-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B (apoB). Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) selectively binds LDL, we hypothesized that it can also be associated with Lp(a) in plasma. Objective 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 co-expression of human apo(a) and human apoB). Methods and Results We show that PCSK9 is physically associated with Lp(a) in vivo using three different approaches: (i) Analysis of Lp(a) fractions isolated by ultracentrifugation; (ii) Immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (iii) 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) vs. LDL (1.7-fold increase) was seen in subjects with high Lp(a) and normal LDL. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels. Conclusions 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.

Development of proprotein convertase subtilisin/kexin type 9 inhibitors and the clinical potential of monoclonal antibodies in the management of lipid disorders

“…Analysis of Lp (a) fraction by ultracentrifugation, immunoprecipitation and ELISA quantification has shown a strong physical association between Lp (a) and PCSK9 in plasma 19. Lp (a) levels are genetically determined.…”

Targeting low‐density lipoprotein cholesterol with PCSK9 inhibitors

“…While PCSK9 levels correlate with elevated Lp(a) levels, the mechanism underlying this association remains unclear . It is unknown whether PCSK9 plays a role in the reported association between Lp(a) and atherosclerotic cardiovascular disease and aortic valve calcification.…”

“…21 While PCSK9 levels correlate with elevated Lp(a) levels, the mechanism underlying this association remains unclear. 22 It is unknown whether PCSK9 plays a role in the reported association between Lp(a) and atherosclerotic cardiovascular disease and aortic valve calcification. Interestingly, loss-of-function PCSK9 mutation carriers demonstrate a lower risk of aortic valve disease, which is independent of Lp(a) levels.…”

PCSK9 and Lipoprotein(a)

“…There has to be. In this issue of Circulation Research, Tavori et al 25 hypothesized that because Lp(a) is a variant of LDL, it too binds and sequesters some amount of PCSK9 in serum. Interestingly, it does.…”