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  • Laaksonen, ReijoResearch Unit, University Hospital of Tampere, Tampere, Finland (author)

A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle

  • Article/chapterEnglish2006

Publisher, publication year, extent ...

  • 2006-12-20
  • PLOS,2006
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:oru-70902
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-70902URI
  • https://doi.org/10.1371/journal.pone.0000097DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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 q-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.

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  • Katajamaa, MikkoTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Päivä, HannuDepartment of Internal Medicine, University Hospital of Tampere, Tampere, Finland (author)
  • Sysi-Aho, MarkoVTT Technical Research Centre of Finland, Espoo, Finland (author)
  • Saarinen, LilliTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Junni, PäiviTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Lütjohann, DieterDepartment of Clinical Pharmacology, University of Bonn, Bonn, Germany (author)
  • Smet, JoélDepartment of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium (author)
  • Van Coster, RudyDepartment of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium (author)
  • Seppänen-Laakso, TuulikkiVTT Technical Research Centre of Finland, Espoo, Finland (author)
  • Lehtimäki, TerhoLaboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere, Finland, Centre for Laboratory Medicine, University Hospital of Tampere, Tampere, Finland; Medical School, University of Tampere, Tampere, Finland (author)
  • Soini, JuhaniTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (author)
  • Oresic, Matej,1967-VTT Technical Research Centre of Finland, Espoo, Finland(Swepub:oru)moc (author)
  • Research Unit, University Hospital of Tampere, Tampere, FinlandTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland (creator_code:org_t)

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  • In:PLOS ONE: PLOS11932-6203

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