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Am J Transl Res. 2018 Dec 15;10(12):4350-4366. eCollection 2018.

Exosomes derived from cardiomyocytes promote cardiac fibrosis via myocyte-fibroblast cross-talk.

Author information

1
Department of Cardiovascular Disease, Shanghai East Hospital, School of Medicine, Tongji University 150 Jimo Rd, Pudong New District, Shanghai 200120, P. R. China.
2
Department of Cardiovascular Disease, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University 1665 Kongjiang Street, Shanghai 200092, P. R. China.
3
Department of Cardiovascular Disease, Shangrao People's Hospital Jiangxi Province 334000, P. R. China.

Abstract

Cardiac fibrosis is primarily mediated by activated fibroblasts. However, cardiomyocytes have also been implicated in facilitating the fibrotic response. We aimed to explore how cardiomyocyte-derived exosomes affect fibroblasts. We measured cardiac-specific microRNA levels in two rat models of cardiac fibrosis to find out which microRNA was involved in the common mechanisms of cardiac fibrosis. Then, we isolated exosomes from cardiomyocytes and measured their effects on fibroblast proliferation and differentiation into myofibroblasts. We used a microRNA antagomir and an AAV9 microRNA sponge delivery system to inhibit cardiac microRNA in vivo. We then transfused cardiomyocyte-derived exosomes into normal rats to determine the functional effects of the exosomes. miR-208a was upregulated in cardiomyocytes and cardiomyocyte-derived exosomes from both models of cardiac fibrosis and could be transferred into cardiac fibroblasts via the exosomes. The miR-208a-containing exosomes contributed to increased fibroblast proliferation and differentiation into myofibroblasts, an effect that was attenuated by the miR-208a antagomir. When miR-208a was inhibited in vivo, cardiac function improved and cardiac fibrosis was alleviated in post-myocardial-infarction rats. The transfusion of miR-208a-containing exosomes into normal rats resulted in worsened cardiac function. We identified Dyrk2 as the target gene of miR-208a. Cardiomyocytes participate in cardiac fibrosis by secreting exosomes containing miR-208a, which increases fibroblast proliferation and differentiation into myofibroblasts.

KEYWORDS:

Cardiomyocyte; Dyrk2; exosomes; fibroblast; miR-208a

PMID:
30662677
PMCID:
PMC6325490

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