Preconditioning via angiotensin type 2 receptor activation improves therapeutic efficacy of bone marrow mononuclear cells for cardiac repair

PLoS One. 2013 Dec 10;8(12):e82997. doi: 10.1371/journal.pone.0082997. eCollection 2013.

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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / chemistry
  • Animals
  • Apoptosis
  • Bone Marrow Cells / cytology*
  • Cell Transplantation
  • Coculture Techniques
  • Echocardiography
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Inflammation
  • Leukocytes, Mononuclear / cytology*
  • Male
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / cytology
  • Neovascularization, Physiologic
  • Nitric Oxide / chemistry
  • Nitric Oxide Synthase Type III / metabolism
  • Oligopeptides / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / agonists
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Stem Cell Transplantation
  • Tetrazoles / chemistry
  • Valine / analogs & derivatives
  • Valine / chemistry
  • Valsartan
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Agtr1a protein, rat
  • Oligopeptides
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Vascular Endothelial Growth Factor A
  • Angiotensin II
  • CGP 42112A
  • Nitric Oxide
  • Valsartan
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Extracellular Signal-Regulated MAP Kinases
  • Valine

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No.31000650 and 81170308), International Joint Research Project of National Natural Science Foundation of China (No.81128003), International Cooperation Major Foundation of Zhejiang Province (No. 2009C14009), Project of Health Bureau of Zhejiang Province (No 2011ZDA010) and Shanghai Pujiang Program (13PJ1405800). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.