Theranostics 2018; 8(8):2079-2093. doi:10.7150/thno.21895

Research Paper

Coronary Serum Exosomes Derived from Patients with Myocardial Ischemia Regulate Angiogenesis through the miR-939-mediated Nitric Oxide Signaling Pathway

Hao Li1*, Yiteng Liao1*, Lei Gao2, Tao Zhuang2, Zheyong Huang3, Hongming Zhu2✉, Junbo Ge1,3✉

1. Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
2. Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
3. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
*Hao Li and Yiteng Liao contributed equally to this work.

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Citation:
Li H, Liao Y, Gao L, Zhuang T, Huang Z, Zhu H, Ge J. Coronary Serum Exosomes Derived from Patients with Myocardial Ischemia Regulate Angiogenesis through the miR-939-mediated Nitric Oxide Signaling Pathway. Theranostics 2018; 8(8):2079-2093. doi:10.7150/thno.21895. Available from http://www.thno.org/v08p2079.htm

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Abstract

Rationale: Angiogenesis is a crucial step towards tissue repair and regeneration after ischemia. The role of circulating exosomes in angiogenic signal transduction has not been well elucidated. Thus, this study aims to investigate the effects of coronary serum exosomes from patients with myocardial ischemia on angiogenesis and to elucidate the underlying mechanisms.

Methods and Results: The patients were enrolled according to the inclusion and exclusion criteria. Coronary blood was obtained from the angiography catheter. Serum exosomes were purified and characterized by their specific morphology and surface markers. In vitro analysis showed that compared to exosomes from healthy controls (con-Exo), exosomes from patients with myocardial ischemia (isc-Exo) enhanced endothelial cell proliferation, migration and tube formation. In a mouse hind-limb ischemia model, blood perfusion and histological staining demonstrated that isc-Exo significantly promoted blood flow recovery and enhanced neovascularization compared to con-Exo. Further, we revealed that cardiomyocytes, but not cardiac fibroblasts or endothelial cells, were initiated to release exosomes under ischemic stress; cardiomyocytes might be the source of bioactive exosomes in coronary serum. In addition, microarray analysis indicated that miR-939-5p was significantly down-regulated in isc-Exo. By knockdown and overexpression analyses, we found that miR-939-5p regulated angiogenesis by targeting iNOS. miR-939-5p inhibited both iNOS's expression and its activity, attenuated endothelial NO production, and eventually impaired angiogenesis.

Conclusions: Exosomes derived from patients with myocardial ischemia promote angiogenesis via the miR-939-iNOS-NO pathway. Our study highlights that coronary serum exosomes serve as an important angiogenic messenger in patients suffering from myocardial ischemia.

Keywords: exosomes, myocardial ischemia, angiogenesis, miR-939-5p