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. Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSC^ATV-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, MSC^ATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSC^ATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSC^ATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSC^ATV-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 MSC^ATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSC^ATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19. 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 MSC^ATV-Exo in promoting angiogenesis.

Background: Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs. Methods: Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay. Results: We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo. Conclusions: Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.

Acute myocardial infarction (AMI) has become a major cause of hospitalization and mortality in China. There has been limited data to date available to characterize AMI presentation, contemporary patterns of medical care, and outcomes in China. The CAMI Registry is a national project with the objectives to timely obtain real-world knowledge about AMI patients and to provide the platform for clinical research, guide preventive measures and care quality improvement efforts in China. The CAMI registry is a prospective, nationwide, multicenter observational study for AMI patients. The registry includes three levels of hospitals (representing typical Chinese governmental and administrative models) from all provinces and municipalities throughout Mainland China except Hong Kong and Macau. Sites were instructed to enroll consecutive patients with a primary diagnosis of AMI. Clinical data, treatments, outcomes and cost are collected by local investigators and captured electronically, with a standardized set of variables and standard definitions, and rigorous data quality control. Post-discharge patient follow-up to 2 years is planned. The CAMI Registry was launched in January 2013. A total of 108 hospitals have participated in the registry so far. As of September 2014, 26,103 patients with AMI were registered. The CAMI registry represents a well-supported and the largest national long-term registry-research-education platform for surveillance, research, prevention and care improvement for AMI in China, the world's most populous nation. The broad representation of all provinces and different-level hospitals will allow for the exploration of AMI across diverse geographic regions and economic circumstances.

Acute myocardial infarction (AMI) is one of the leading causes of mortality around the world, and the inflammatory response plays a pivotal role in the progress of myocardial necrosis and ventricular remodeling, dysfunction and heart failure after AMI. Therapies aimed at modulating immune response after AMI on a molecular and cellular basis are urgently needed. Exosomes are a type of extracellular vesicles which contain a large amount of biologically active substances, like lipids, nucleic acids, proteins and so on. Emerging evidence suggests key roles of exosomes in immune regulation post AMI. A variety of immune cells participate in the immunomodulation after AMI, working together to clean up necrotic tissue and repair damaged myocardium. Stem cell therapy for myocardial infarction has long been a research hotspot during the last two decades and exosomes secreted by stem cells are important active substances and have similar therapeutic effects of immunomodulation, anti-apoptosis, anti-fibrotic and angiogenesis to those of stem cells themselves. Therefore, in this review, we focus on the characteristics and roles of exosomes produced by both of endogenous immune cells and exogenous stem cells in myocardial repair through immunomodulation after AMI.