The interplay between HIF-1α and long noncoding GAS5 regulates the JAK1/STAT3 signalling pathway in hypoxia-induced injury in myocardial cells

Abstract

Background: Long non-coding RNA (lncRNA) GAS5 is associated with hypoxia-induced diseases whereas hypoxia-inducible factor-1α (HIF-1α) plays an important role in hypoxic injury of cells. The current study explores the regulatory functions of GAS5/HIF-1α which co-play in anoxic injury among rat cardiomyocytes H9C2 cells.Methods: Hypoxia in vitro model was established through anoxic incubation while normal culture of H9C2 cells was considered as control. The expression levels of GAS5 and HIF-1α were quantified through RT-qPCR. CCK-8 was applied to determine cell viability. Cell apoptosis rate was calculated using flow cytometry whereas inflammatory cytokines were detected using ELISA method. The impact of downregulating GAS5 or HIF-1α or both upon hypoxic cells was assessed on the basis of changes in cell viability, apoptosis, and inflammatory response. The activity of JAK1/STAT3 signaling was evaluated through RT-qPCR for mRNA expression. AG490 was introduced to inactivate JAK1/STAT3 pathway and to unveil the impact of JAK1/ STAT3 signaling on GAS5/HIF-1α and cell viability, apoptosis and inflammation in hypoxic cells. Results:The results infer that hypoxia suppressed cell viability, promoted inflammation and apoptosis among H9C2 cells. GAS5 or HIF-1α recorded higher expression in hypoxia-induced cells whereas the cell viability got restored with reduction in inflammation and apoptosis. The downregulation of HIF-1α enhanced the protective effect of knocking down GAS5 in hypoxia H9C2 cells. JAK1/STAT3 signaling pathway got activated in hypoxic cells and was regulated by GAS5 and HIF-1α. The inhibition of signaling pathway increased the cell viability but it decreased both inflammation and apoptosis.Conclusions: GAS5 and HIF-1α could regulate hypoxic injury in H9C2 cells through JAK1/STAT3 signaling pathway. This scenario suggests that the inhibitors of GAS5 and HIF-1α may synergize with AG-490 to protect myocardial cells from hypoxic injury.

Bone marrow mesenchymal stem cells-derived exosomal lncRNA GAS5 mitigates heart failure by inhibiting UL3/Hippo pathway-mediated ferroptosis

“…Wu et al [ 26 ] reported that silencing of GAS5 ameliorated myocardial IR injury in hypoxia/reoxygenation-treated cardiomyocytes and IR rats [ 26 ]. Li et al [ 49 ] revealed that silencing GAS5 inhibits inflammation and apoptosis in hypoxia-treated cardiomyocytes [ 49 ]. Moreover, GAS5 can mediate oxidative stress in cardiac vascular injury.…”

“…Mao et al [ 13 ] report that lncRNA KLF3-AS1 in MSC-Exos attenuates myocardial infarction by inhibiting pyroptosis in cardiomyocytes [ 13 ]. Li et al [ 49 ] observe that lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) in BMSC-Exos protects cardiomyocytes against ischemia/reperfusion (IR) injury [ 14 ]. However, the lncRNAs involved in the action mechanisms of BMSC-Exos in HF have rarely been reported.…”