Silencing of the long non-coding RNA MEG3 suppresses the apoptosis of aortic endothelial cells in mice with chronic intermittent hypoxia via downregulation of HIF-1α by competitively binding to microRNA-135a

Abstract

Background: Chronic intermittent hypoxia (CIH) involves substantial cortico-hippocampal injury, causing impairments of neurocognitive, respiratory, and cardiovascular functions. Long non-coding RNAs (lncRNAs) participate in CIH functions and development. Therefore, we explored the mechanisms involving lncRNA maternally expressed gene 3 (MEG3) regulating the aortic endothelial function of CIH mice via regulation of microRNA-135a (miR-135a) and the hypoxia-inducible factor (HIF)-1α. Methods: Expression of MEG3, miR-135a, and HIF-1α in CIH mice and CIH-treated cells was detected.Then, the apoptosis and proliferation of the aortic endothelial cells were examined to verify whether miR-135a and HIF-1α participated in CIH. Next, the interactions between MEG3, miR-135a, and HIF-1α were explored. Later, the effects of MEG3/miR-135a/HIF-1α on the expression of proliferation-and apoptosisrelated factors and aortic injury were investigated via gain-and loss-of function studies both in vivo and in vitro.Results: MEG3 and HIF-1α were highly expressed while miR-135a was poorly expressed in CIH mice and CIH-modeled cells. Moreover, miR-135a targeted HIF-1α to promote cell proliferation and inhibit apoptosis. MEG3 regulated HIF-1α expression by competitively binding to miR-135a. More importantly, we found that the silencing of MEG3/HIF-1α and the overexpression of miR-135a inhibited the apoptosis and injury of aortic endothelial cells while promoting cell proliferation in CIH mice. Conclusions: Altogether, silencing of MEG3 suppressed the aortic endothelial injury and cell apoptosis in CIH mice by downregulating HIF-1α through sponging miR-135a, providing evidence of a potential therapeutic target for CIH.

Depletion of lncRNA MEG3 Ameliorates Imatinib‐Induced Injury of Cardiomyocytes via Regulating miR‐129‐5p/HMGB1 Axis

“…MEG3 has also been reported to be involved in hypoxia-induced myocardial injury. For example, knockdown of MEG3 inhibits hypoxia-induced apoptosis of aortic endothelial cells through repressing HIF-1α expression [22]. Another study reports that knockdown of MEG3 attenuates hypoxia-induced cardiomyocyte injury in rats by downregulating the expression of transient receptor potential cation channel subfamily V member 4 [23].…”

Role of epigenetic abnormalities and intervention in obstructive sleep apnea target organs

“…Another experiment focused on aortic endothelial dysfunction in CIH and demonstrated that lncRNA maternally expressed gene 3 (MEG3) changed the expression of HIF-1α by competitively binding to miR-135a and that apoptosis and injury of aortic endothelial cells could be suppressed by silencing MEG3. [ 135 ] Zhang et al 's [ 136 ] group suggested that upregulated lncRNA CPS1 intronic transcript 1 might allay PHT in OSA by reducing IL-1β expression, the mechanism of which was involved with suppressive HIF-1 transcriptional activity and the NF-κB signaling pathway. However, they did not consider possible potential miRNA regulation.…”

“…Du et al [110] explored the roles of ncRNAs in T2DM with OSA and designed them to solve related cognitive disorders, and their outcomes indicated that lncRNA metastasis-associated lung adenocarcinoma transcript 1 affected the NLRP3/IL-1b pathway in the hippocampus by sponging miR-224-5p. Another experiment focused on aortic endothelial dysfunction in CIH and demonstrated that lncRNA maternally expressed gene 3 (MEG3) changed the expression of HIF-1α by competitively binding to miR-135a and that apoptosis and injury of aortic endothelial cells could be suppressed by silencing MEG3 [135] . Zhang et al 's [136] group suggested that upregulated lncRNA CPS1 intronic transcript 1 might allay PHT in OSA by reducing IL-1β expression, the mechanism of which was involved with suppressive HIF-1 transcriptional activity and the NF-κB signaling pathway.…”

Hypoxia related long non-coding RNAs in ischemic stroke

“…Furthermore, the expression of c-Jun transcription factor-dependent PHPP1 is reduced, which ultimately leads to the reduction of PHPP1-mediated HIF translation [ 81 ]. Under hypoxia, the effect of silencing MEG3 and HIF's competitive binding to microRNA-135a is weakened, thereby enhancing the inhibitory effect of microRNA-135a on HIF, reducing HIF expression, and ultimately promoting cell proliferation and inhibiting apoptosis [ 82 ]. The expression of MEG3 in IS is positively correlated with the infarct size of the patient, leading to a poor prognosis of the patient [ 83 ].…”