TY - JOUR
T1 - Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9
AU - Ason, Brandon
AU - Tep, Samnang
AU - Davis, Harry R.
AU - Xu, Yiming
AU - Tetzloff, Glen
AU - Galinski, Beverly
AU - Soriano, Ferdie
AU - Dubinina, Natalya
AU - Zhu, Lei
AU - Stefanni, Alice
AU - Wong, Kenny K.
AU - Tadin-Strapps, Marija
AU - Bartz, Steven R.
AU - Hubbard, Brian
AU - Ranalletta, Mollie
AU - Sachs, Alan B.
AU - Flanagan, W. Michael
AU - Strack, Alison
AU - Kuklin, Nelly A.
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - Cholesterol/metabolism
KW - Drug therapy
KW - Gene expression
UR - http://www.scopus.com/inward/record.url?scp=79953317222&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953317222&partnerID=8YFLogxK
U2 - 10.1194/jlr.M013664
DO - 10.1194/jlr.M013664
M3 - Article
C2 - 21262787
AN - SCOPUS:79953317222
SN - 0022-2275
VL - 52
SP - 679
EP - 687
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 4
ER -