Key result
Exosomes derived from atorvastatin-pretreated mesenchymal stem cells significantly improved left ventricular ejection fraction (54.75% vs 27.52%, p<0.001) compared to PBS in a rat model of acute myocardial infarction.
Why the study?
To determine whether exosomes derived from atorvastatin-pretreated mesenchymal stem cells exhibit enhanced cardioprotection in acute myocardial infarction and to investigate the underlying mechanisms.
Atorvastatin pretreatment of mesenchymal stem cells enhances the cardioprotective efficacy of their secreted exosomes in acute myocardial infarction via up-regulation of lncRNA H19.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for exosome therapy in AMI; leaves open translation from this animal model.
AIMS: Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms. METHODS AND RESULTS: Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19. CONCLUSION: Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.
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Huang et al. (2019) studied Acute myocardial infarction. Exosomes derived from atorvastatin-pretreated mesenchymal stem cells (MSCATV-Exo) vs. PBS or exosomes from non-pretreated MSCs was evaluated on Left ventricular ejection fraction (LVEF) at 4 weeks (p=<0.001). Exosomes derived from atorvastatin-pretreated mesenchymal stem cells significantly improved left ventricular ejection fraction (54.75% vs 27.52%, p<0.001) compared to PBS in a rat model of acute myocardial infarction.
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