title: Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: the role of the RhoA/ROCK/ERK pathway.
abstract: BACKGROUND
  Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of statins. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo.
  
  
  RESULTS
  Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. ATV facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. ATV inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI.
  
  
  CONCLUSIONS
  ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China. Electronic address: yangyjfw@126.com.
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Qiu-Ting
authors.initials: QT
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Tian-Jie
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Xi-Mei
authors.initials: XM
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jin
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology / Q000628:therapy*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014463:Ultrasonography; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Acute myocardial infarction; Atorvastatin; Extracellular regulated protein kinase; Fasudil; Mesenchymal stem cells; Rho-associated coiled-coil forming kinase