Izadpanah Reza, Schächtele Deborah J, Pfnür Andreas B, Lin Dong, Slakey Douglas P, Kadowitz Philip J, Alt Eckhard U
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.
Applied Stem Cell Laboratory, Heart and Vascular Institute, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana;
Am J Physiol Cell Physiol. 2015 Oct 15;309(8):C522-31. doi: 10.1152/ajpcell.00406.2014. Epub 2015 Jul 29.
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.
他汀类药物可减少动脉粥样硬化事件和心血管疾病死亡率。其副作用包括记忆力减退、肌病、白内障形成以及糖尿病风险增加。由于心血管疾病死亡率与斑块不稳定性相关，而斑块不稳定性取决于纤维帽的完整性，我们推测抑制间充质干细胞（MSC）向巨噬细胞分化的潜能，有助于解释他汀类药物对心血管疾病死亡率长期以来已知但了解较少的“非脂质相关”或多效性益处。在本研究中，用临床相关浓度的阿托伐他汀或普伐他汀处理MSC，并评估其增殖、分化潜能和基因表达谱。两种他汀类药物均降低了MSC的总体生长速率。特别是，他汀类药物降低了MSC向巨噬细胞分化的潜能，同时对巨噬细胞功能无直接影响。这些发现表明，MSC向巨噬细胞分化能力有限可能导致动脉斑块内巨噬细胞密度降低、炎症减轻，进而增强斑块稳定性。这将解释心血管事件中与脂质无关的减少情况。不利的一面是，他汀类药物损害了MSC的成骨和成软骨分化潜能，并增加了细胞衰老和凋亡，这表现为p16、p53以及半胱天冬酶3、8和9的上调。他汀类药物还损害了包括XRCC4、XRCC6和Apex1在内的DNA修复基因的表达。虽然对巨噬细胞分化的影响解释了他汀类药物的有益作用，但其对干细胞其他生物学特性的影响为其不良临床效应提供了新的解释。
