title: Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase.
abstract: BACKGROUND
  In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury.
  
  
  RESULTS
  42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both "perfusion" defined by Single-Photon Emission Computed Tomography (-6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and "metabolism" defined by Positron Emission Tomography (-3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA.
  
  
  CONCLUSIONS
  Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.
authors.affiliation: Coronary Heart Disease Center, Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Yang
authors.forename: Qiu-Ting
authors.initials: QT
authors.lastname: Dong
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.forename: Run-Lin
authors.initials: RL
authors.lastname: Gao
authors.forename: Shu-Bin
authors.initials: SB
authors.lastname: Qiao
authors.forename: Rui
authors.initials: R
authors.lastname: Shen
authors.forename: Zuo-Xiang
authors.initials: ZX
authors.lastname: He
authors.forename: Min-Jie
authors.initials: MJ
authors.lastname: Lu
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Zhao
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D013552:Swine; D015899:Tomography, Emission-Computed, Single-Photon; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D009569:Nitric Oxide; D002097:C-Reactive Protein; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III