Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2011-3-24
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Anticholesteremic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins B, http://linkedlifedata.com/resource/pubmed/chemical/Azetidines, http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol, http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol, LDL, http://linkedlifedata.com/resource/pubmed/chemical/Fluorobenzenes, http://linkedlifedata.com/resource/pubmed/chemical/Pcsk9 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering, http://linkedlifedata.com/resource/pubmed/chemical/Serine Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides, http://linkedlifedata.com/resource/pubmed/chemical/Triglycerides, http://linkedlifedata.com/resource/pubmed/chemical/ezetimibe, http://linkedlifedata.com/resource/pubmed/chemical/rosuvastatin
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2275
pubmed:author
pubmed:issnType
Print
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
679-87
pubmed:meshHeading
pubmed-meshheading:21262787-Animals, pubmed-meshheading:21262787-Anticholesteremic Agents, pubmed-meshheading:21262787-Apolipoproteins B, pubmed-meshheading:21262787-Azetidines, pubmed-meshheading:21262787-Cholesterol, pubmed-meshheading:21262787-Cholesterol, LDL, pubmed-meshheading:21262787-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:21262787-Fluorobenzenes, pubmed-meshheading:21262787-Hypercholesterolemia, pubmed-meshheading:21262787-Mice, pubmed-meshheading:21262787-Mice, Inbred C57BL, pubmed-meshheading:21262787-Pyrimidines, pubmed-meshheading:21262787-RNA, Small Interfering, pubmed-meshheading:21262787-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:21262787-Serine Endopeptidases, pubmed-meshheading:21262787-Sulfonamides, pubmed-meshheading:21262787-Triglycerides
pubmed:year
2011
pubmed:articleTitle
Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9.
pubmed:affiliation
Sirna Therapeutics/Merck & Co. Inc, San Francisco, CA 94158, USA. brandon_ason@merck.com
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't