Atorvastatin Treatment of Rats with Ischemia-Reperfusion Injury Improves Adipose-Derived Mesenchymal Stem Cell Migration and Survival via the SDF-1α/CXCR-4 Axis

Anping Cai,Yingling Zhou,Weiyi Mai,Yuli Huang,Danqing Yu,Shaoqi Rao,Ruofeng Qiu,Dongdan Zheng,Yugang Dong,Liwen Li,Rajesh Gopalrao Katare

doi:10.1371/journal.pone.0079100

Abstract

BackgroundAdipose-derived mesenchymal stem cells (ASCs) transplantation is a promising approach for myocardium repair. Promotion of ASCs migration and survival is the key for improving ASCs efficiency. SDF-1α is a critical factor responsible for ASCs migration and survival. Atorvastatin (Ator) is capable of up-regulating SDF-1α. Therefore, we're going to investigate whether ASCs migration and survival could be improved with atorvastatin.Methods In vitro study, cardiomyocytes were subjected to anoxia-reoxygenation injury and subsequently divided into different groups: group blank control, Ator, Ator plus L-NAME (A+L-NAME) and Ator plus AMD3100 (A+AMD3100).When migration analysis completed, cardiomyocytes were used for subsequent analyses. In vivo study, rats underwent ischemia-reperfusion injury were assigned into different groups corresponding to in vitro protocols. ASCs were transplanted on the seventh day of atorvastatin therapy. Seven days later, the rates of migration, differentiation and apoptosis were evaluated.ResultsCompared with other groups, ASCs migration in vitro was significantly improved in group Ator, which was dependent on SDF-1α/CXCR-4 coupling. Results of in vivo study were consistent with that of in vitro study, further supporting the notion that the efficacy of atorvastatin on ASCs migration improvement was related to SDF-1α/CXCR-4 axis. Higher vessel density in group Ator might be another mechanism responsible for migration improvement. Concomitantly, apoptosis was significantly reduced in group Ator, whereas no significant difference of differentiation was found.ConclusionMigration and survival of ASCs could be improved by atorvastatin under ischemia-reperfusion injury, which were ascribed to SDF-1α/CXCR-4 axis.

Highlights

Congestive heart failure (CHF) is still the leading cause of morbidity and mortality worldwide [1,2]
Immuno-phenotype and Expression of CXCR4 of Adipose-derived mesenchymal stem cells (ASCs) As shown in Figure 1 panel (b), a vast majority of the fourth passage ASCs were positive for ASCs specific markers CD29 and CD44, while only minority of ASCs were positive for endothelial cells marker CD31 and hematopoietic cells marker CD45
Our present study showed that compared with blank control group, atorvastatin treatment significantly promoted ASCs oriented migration and reduced ASCs apoptosis in rat with ischemiareperfusion injury

Summary

Introduction

Congestive heart failure (CHF) is still the leading cause of morbidity and mortality worldwide [1,2]. Ischemic heart disease characterized by myocardial loss and cardiac remodeling is the major cause of CHF [3,4]. A variety of strategies have been applied to improve outcome of ischemic heart disease, and one of the most promising and attractive approaches is adipose-derived mesenchymal stem cells (ASCs) transplantation [5,6,7]. With peripheral infusion, the amount of ASCs migrating to targeted tissue is far from enough to fully conduct repair and re-construction. Adipose-derived mesenchymal stem cells (ASCs) transplantation is a promising approach for myocardium repair. SDF-1a is a critical factor responsible for ASCs migration and survival. We’re going to investigate whether ASCs migration and survival could be improved with atorvastatin

Methods

Results

Discussion

Conclusion