A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-Induced Changes in Muscle

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dc.contributor.author Laaksonen, Reijo -
dc.contributor.author Katajamaa, Mikko -
dc.contributor.author Päivä, Hannu -
dc.contributor.author Lehtimäki, Terho (Tay) -
dc.date.accessioned 2012-06-17T20:14:24Z
dc.date.available 2012-06-16 09:17:10 -
dc.date.available 2012-06-17T20:14:24Z
dc.date.issued 2006 -
dc.identifier.issn 1932-6203 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/65911
dc.description Public Library of Science -
dc.description.abstract Background Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. Methodology We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo. Principal Findings High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate 1q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. Conclusions High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity. -
dc.language.iso en -
dc.title A Systems Biology Strategy Reveals Biological Pathways and Plasma Biomarker Candidates for Potentially Toxic Statin-Induced Changes in Muscle -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal article| -
dc.identifier.urn urn:nbn:uta-3-670 -
dc.identifier.doi 10.1371/journal.pone.0000097 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Sisätaudit | en=Internal Medicine| -
dc.journal.title PLoS ONE -
dc.journal.volume 1 -
dc.journal.number 1 -
dc.journal.volumepagerange 1-9 -
dc.oldstats 60 -

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