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Cardiovasc Res. 2019 May 22. pii: cvz139. doi: 10.1093/cvr/cvz139. [Epub ahead of print]

Atorvastatin Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells Derived Exosomes in Acute Myocardial Infarction via Up-regulating Long Non-coding RNA H19.

Author information

1
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PRC.
2
McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
4
Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Chapel Hill and Raleigh, North Carolina, USA.

Abstract

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 ICAM-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.

CONCLUSIONS:

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.

KEYWORDS:

MSCs; atorvastatin; exosomes; lncRNA H19; myocardial infarction

PMID:
31119268
DOI:
10.1093/cvr/cvz139

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