title: The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleiotropic beneficial and adverse clinical effects.
abstract: Statins reduce atherosclerotic events and cardiovascular mortality. Their side effects include memory loss, myopathy, cataract formation, and increased risk of diabetes. As cardiovascular mortality relates to plaque instability, which depends on the integrity of the fibrous cap, we hypothesize that the inhibition of the potential of mesenchymal stem cells (MSCs) to differentiate into macrophages would help to explain the long known, but less understood "non-lipid-associated" or pleiotropic benefit of statins on cardiovascular mortality. In the present investigation, MSCs were treated with atorvastatin or pravastatin at clinically relevant concentrations and their proliferation, differentiation potential, and gene expression profile were assessed. Both types of statins reduced the overall growth rate of MSCs. Especially, statins reduced the potential of MSCs to differentiate into macrophages while they exhibited no direct effect on macrophage function. These findings suggest that the limited capacity of MSCs to differentiate into macrophages could possibly result in decreased macrophage density within the arterial plaque, reduced inflammation, and subsequently enhance plaque stability. This would explain the non-lipid-associated reduction in cardiovascular events. On a negative side, statins impaired the osteogenic and chondrogenic differentiation potential of MSCs and increased cell senescence and apoptosis, as indicated by upregulation of p16, p53 and Caspase 3, 8, and 9. Statins also impaired the expression of DNA repair genes, including XRCC4, XRCC6, and Apex1. While the effect on macrophage differentiation explains the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.
authors.affiliation: Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana; Department of Surgery, Tulane University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: Reza
authors.initials: R
authors.lastname: Izadpanah
authors.affiliation: Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Schächtele
authors.affiliation: Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Pfnür
authors.affiliation: Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Surgery, Tulane University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Slakey
authors.affiliation: Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
authors.affiliation: Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana; ealt@tulane.edu.
authors.forename: Eckhard U
authors.initials: EU
authors.lastname: Alt
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D000368:Aged; D000375:Aging; D002453:Cell Cycle; D002478:Cells, Cultured; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: atherosclerotic plaque; cardiovascular events; macrophages; statin drugs; stem cells