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 reduce the overall growth rate of MSCs. Especially, statins reduce the potential of MSCs to differentiate into macrophages while they exhibit 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 impair the osteogenic and chondrogenic differentiation potential of MSCs, increase cell senescence and apoptosis as indicated by up-regulation of p16, p53, 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 explain the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.
- Stem Cells
- Atherosclerotic Plaque
- Statin Drugs
- Cardiovascular Events
- Copyright © 2015, American Journal of Physiology - Cell Physiology