Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9.

Abstract	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.
Authors	Brandon Ason, Samnang Tep, Harry R Davis Jr, Yiming Xu, Glen Tetzloff, Beverly Galinski, Ferdie Soriano, Natalya Dubinina, Lei Zhu, Alice Stefanni, Kenny K Wong, Marija Tadin-Strapps, Steven R Bartz, Brian Hubbard, Mollie Ranalletta, Alan B Sachs, W Michael Flanagan, Alison Strack, Nelly A Kuklin
Journal	Journal of lipid research (J Lipid Res) Vol. 52 Issue 4 Pg. 679-87 (Apr 2011) ISSN: 1539-7262 [Electronic] United States
PMID	21262787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Anticholesteremic Agents Apolipoproteins B Azetidines Cholesterol, LDL Fluorobenzenes Pyrimidines RNA, Small Interfering Sulfonamides Triglycerides Rosuvastatin Calcium Cholesterol Pcsk9 protein, mouse Proprotein Convertase 9 Proprotein Convertases Serine Endopeptidases Ezetimibe
Topics	Animals Anticholesteremic Agents (therapeutic use) Apolipoproteins B (blood) Azetidines (therapeutic use) Cholesterol (blood) Cholesterol, LDL (blood) Enzyme-Linked Immunosorbent Assay Ezetimibe Fluorobenzenes (therapeutic use) Hypercholesterolemia (blood, drug therapy, therapy) Mice Mice, Inbred C57BL Proprotein Convertase 9 Proprotein Convertases Pyrimidines (therapeutic use) RNA, Small Interfering (genetics, physiology) Reverse Transcriptase Polymerase Chain Reaction Rosuvastatin Calcium Serine Endopeptidases (genetics, metabolism) Sulfonamides (therapeutic use) Triglycerides (blood)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!