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

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. Hypoxiaconditioned 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.

Long non‐coding RNA UCA1 correlates with elevated disease severity, Th17 cell proportion, inflammatory cytokines, and worse prognosis in acute ischemic stroke patients

“…[7][8][9][10] More interestingly, accumulating evidence suggests the crucial role of lncRNA UCA1 in various cadio-cerebovascular diseases. [11][12][13] For instance, lncRNA UCA1 regulates microRNA (miR)-18a expression to promote hypoxia injury and neural cell apoptosis in the cell model of cerebral ischemia. 14 plays an important role in the pathogenesis of AIS since inflammation leads to unstable atherosclerotic plaque with higher risk of rupture.…”

“…In the clinical practice, lncRNA UCA1 expression is upregulated in acute myocardial infraction (AMI) patients, which shares similar pathophysiological mechanism as AIS since both of these two diseases characterized by the blockage of blood vessels due to atherosclerosis plaque formation. 12 In addition, we performed a preliminary research in a smaller sample size and discovered that lncRNA UCA1 expression was upregulated in tested AIS patients. Based on those abovementioned evidence, we hypothesized that lncRNA UCA1 may play a critical role in AIS.…”

“…cardio-cerebrovascular diseases. For instance, lncRNA UCA1 expression is increased in AMI patients compared to control subjects 12. Another study demonstrates that lncRNA UCA1 expression varies in AMI patients which is reduced initially, then increased in Day 3 after AMI occurrence 19.…”

The Multifunctionality of Exosomes; from the Garbage Bin of the Cell to a Next Generation Gene and Cellular Therapy

“…MSC derived exosomal delivery of lncRNA NEAT was found to enhance recovery of cardiac function in vivo compromised by the drug doxorubicin [76]. Exosome packaged lncRNA UCA1 was shown to function in two differing roles, highlighting the duplicity of many lncRNAs in mechanistic function [77,78]. MSC derived exosomes containing UCA1 have been shown to sponge miR-873 and prevent apoptosis to ultimately aid in cardio-protection in myocardial infarction model of rat.…”

“…MSC derived exosomes containing UCA1 have been shown to sponge miR-873 and prevent apoptosis to ultimately aid in cardio-protection in myocardial infarction model of rat. UCA1 is also found elevated in serum derived exosomes from patients surviving myocardial infarction, suggesting additional clues towards its protective role [77]. However, UCA1 is not always protective.…”