title: Preconditioning via angiotensin type 2 receptor activation improves therapeutic efficacy of bone marrow mononuclear cells for cardiac repair.
abstract: BACKGROUND
  The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation.
  
  
  RESULTS
  Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement.
  
  
  CONCLUSIONS
  Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair.
authors: Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China ; Cardiovascular key lab of Zhejiang Province, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: Yinchuan
authors: Y
authors: Xu
authors: Xinyang
authors: X
authors: Hu
authors: Lihan
authors: L
authors: Wang
authors: Zhi
authors: Z
authors: Jiang
authors: Xianbao
authors: X
authors: Liu
authors: Hong
authors: H
authors: Yu
authors: Zhaocai
authors: Z
authors: Zhang
authors: Huiqiang
authors: H
authors: Chen
authors: Han
authors: H
authors: Chen
authors: Gustav
authors: G
authors: Steinhoff
authors: Jun
authors: J
authors: Li
authors: Jian'an Wang
mesh_terms: D000804:Angiotensin II / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D017690:Cell Transplantation; D018920:Coculture Techniques; D004452:Echocardiography; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008297:Male; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013777:Tetrazoles / Q000737:chemistry; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry; D000068756:Valsartan; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C544067:Agtr1a protein, rat; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; C060894:CGP 42112A; D009569:Nitric Oxide; D000068756:Valsartan; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D014633:Valine