Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873-5p/XIAP axis

Ling Sun,Pengcheng Zhao,Qingjie Wang,Yao Lu,Qiushi Chen,Fengxiang Zhang,Wenwu Zhu,Baohan Fan,Jian Zhang,Yeqian Zhu

doi:10.1038/s41419-020-02783-5

Ling Sun, Pengcheng Zhao + Show 8 more

Open Access

https://doi.org/10.1038/s41419-020-02783-5

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Abstract

Exosomes (Exo) secreted from mesenchymal stem cells (hMSCs) are protective against myocardial injury. The purpose of the study was to investigate the role and mechanisms by which exosomes promote cardiomyocyte survival and function following myocardial infarction (MI). hMSCs were cultured under hypoxic and normoxic conditions. Hypoxia-conditioned hMSC-derived exosomes (Hypo-Exo) and normoxic-conditioned hMSC-derived exosomes (Nor-Exo) were collected and intramyocardially injected into rats with MI. The therapeutic effects of Hypo-Exo and Nor-Exo were evaluated after 4 weeks. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of candidate long noncoding RNA urothelial carcinoma associated 1 (lncRNA-UCA1) in Nor-Exo and Hypo-Exo. Intramyocardial injection of lncRNA-UCA1-knockdown-Hypo-Exo in a rat model of MI was then performed and the cardiac function was characterized. The target and downstream of the molecular mechanism lncRNA-UCA1 was disclosed by luciferase reporter assays and western blot. Circulating exosomal lncRNA-UCA1 level in AMI patients and healthy volunteers was assessed. We found that (1) hMSC exosomal (from hypoxic and normoxic conditions) cardioprotection in vitro and in vivo correlated with the presence of encapsulated lncRNA-UCA1 in exosomes; (2) lncRNA-UCA1 targeted miR-873 via sponging, reducing the latter’s suppressive effects on its target XIAP, and this translated into AMPK phosphorylation and increased level of the antiapoptotic protein BCL2; and (3) plasma derived from patients with AMI contained exosomes enriched with the lncRNA-UCA1, unlike that from normal subjects. This study demonstrates that Hypo-Exo lncRNA-UCA1 plays a cardioprotective role via the miR-873-5p/XIAP axis and circulating exosomal lncRNA-UCA1 may be a promising novel biomarker for the diagnosis of AMI.

Highlights

Ischemic heart disease is a leading cause of death[1] of which acute myocardial infarction (AMI) is an important cause, leading to a poor prognosis[2,3]
Hypoxia exposure, and transfection All cells were incubated at 37 °C in 5% CO2 and 21% O2 under normal condition. human mesenchymal stem cell (hMSC) from healthy adults were purchased from Cambrex BioScience and cultured in αminimal essential medium (α-MEM) with 10% fetal bovine serum (FBS)
Circulating exosomal lncRNAUCA1 may serve as a noninvasive biomarker for AMI diagnosis (Fig. 8h)

Summary

Introduction

Ischemic heart disease is a leading cause of death[1] of which acute myocardial infarction (AMI) is an important cause, leading to a poor prognosis[2,3]. Stent insertion and thrombolysis are the main treatment methods[5,6]. They can be associated with reperfusion injury, including myocardial cell death and microvascular injury[7]. An effective alternative therapy for myocardial infarction (MI) that can reduce cardiomyocyte loss is urgently required. Transplantation of stem cells has been reported to promote cardiac function after MI8. Several studies have confirmed this cardioprotective function of stem cells, largely achieved by secretion of paracrine

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