Abstract
BackgroundThe 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 ResultsAcute 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. ConclusionsPreconditioning 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.
Highlights
Myocardial infarction (MI), a main cause of morbidity and mortality, is characterized by myocardium injury, scar formation, and progressive cardiac dysfunction[1]
The maximal protective effects can be observed when CGP42112A was delivered at a dose of 10nM (P=0.013 vs bone marrow mononuclear cells (BMMNCs) group), while 100 nM CGP42112A treatment exhibited a trend of less beneficial effects compared with at a dose of 10 nM, without reaching a statistical significance (P=0.566 vs 10nM CGP42112A group) (Figure S2 A to F)
The protective effect against apoptosis offered by preconditioned BMMNCs was present when BMMNCs have been preconditioned for 1 hour (P=0.044 vs BMMNCs group) and this protective effect was further enhanced when the time duration increased and reached its peak with 2 hours of CGP42112A pre-treatment (P=0.003 vs BMMNCs group) (Figure S3 A to H)
Summary
Myocardial infarction (MI), a main cause of morbidity and mortality, is characterized by myocardium injury, scar formation, and progressive cardiac dysfunction[1]. Two animal studies has provided evidence that injection of hematopoietic cells or bone marrow stromal cells from AT2R deficient mice led to a significantly neurological deficit in a murine model of brain ischemia compared with cells derived from wide type mice. It appears that AT2R signaling may be required for bone marrow stem cells mediated protection against ischemic brain injury[14,15]. We developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair
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