Research Articles
Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9[S]

https://doi.org/10.1194/jlr.M013664Get rights and content
Under a Creative Commons license
open access

Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfer­ing RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides.

cholesterol/metabolism
drug therapy
gene expression

Cited by (0)

    Abbreviations:

    ALT

    alanine aminotransferase

    APOB

    apolipoprotein B

    AST

    aspartate aminotransferase

    CE

    cholesteryl ester

    DELFIA

    dissociation-enhanced lanthanide fluorescence immunoassay

    FC

    free cholesterol

    H and E

    hematoxylin and eosin

    LDH

    lactate dehydrogenase

    LDL-c

    LDL cholesterol

    LDLr

    LDL receptor

    LNP

    lipid nanoparticle

    NBF

    neutral buffered formalin

    PCSK9

    proprotein convertase subtilisin/kexin type 9

    siRNA

    small interfering RNA

    SREBP-2

    sterol-regulatory-element-binding protein-2

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of eight figures and two tables.

2

B. Ason and S. Tep contributed equally to this work.