title: Statins impair survival of primary human mesenchymal progenitor cells via mevalonate depletion, NF-κB signaling, and Bnip3.
abstract: Circulating progenitor cells of bone marrow origin have been implicated in transplant cardiac allograft vasculopathy (CAV) and cardiac fibrosis. HMG-CoA reductase inhibitors, called "statins," have been shown to impair the progression of CAV and improve patient survival. We examined the in vitro effects of three HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin on the viability of MSCs and expression of nuclear factor kappa B (NF-κB). Mesenchymal stem cells (MSCs) isolated from human patients were treated with atorvastatin, simvastatin, and pravastatin at 0.1, 1.0, or 10 μM ± mevalonate. Human MSC treatment with 1 and 10 μM simvastatin or atorvastatin resulted in progressively reduced cell viability, which was associated with a decline in NF-κB p65. Viability was rescued by co-incubation with mevalonate or by pretreatment with Inhibitor of nuclear factor kappa-B kinase subunit beta (Iκκ-β). Pravastatin did not affect MSC viability or NF-κB expression. Mevalonate depletion through HMG-CoA reductase inhibition impairs the viability of primary human MSC through down-regulating NF-κB.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, Department of Physiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Alison L
authors.initials: AL
authors.lastname: Müller
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Ngo
authors.forename: Kiranjit
authors.initials: K
authors.lastname: Sran
authors.forename: Daniel
authors.initials: D
authors.lastname: Bellan
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Arora
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.forename: Darren H
authors.initials: DH
authors.lastname: Freed
mesh_terms: D000069059:Atorvastatin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C090121:BNIP3 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000069059:Atorvastatin; D019821:Simvastatin; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D017035:Pravastatin; D008798:Mevalonic Acid