KDM3A inhibition attenuates high concentration insulin‑induced vascular smooth muscle cell injury by suppressing MAPK/NF‑κB pathways

Abstract

Previous studies have indicated that lysine (K)-specific demethylase 3A (KDM3A) is associated with diverse diabetes-associated cardiovascular complications in response to high glucose levels. However, the effects of KDM3A on the pathological progression of cardiovascular injuries in response to high insulin levels remain unknown. The present study aimed to explore whether KDM3A knockdown may attenuate high insulin-induced vascular smooth muscle cell (VSMC) dysfunction, and to further investigate the underlying mechanisms. Primary VSMCs were isolated from the thoracic aorta of Sprague-Dawley rats. Lentiviral vectors encoding control-small interfering (si)RNA or KDM3A-siRNA were transduced into VSMCs for 72 h, and cells were subsequently incubated in medium containing 100 nM insulin for a further 5 days. Cellular proli feration, migration and apoptosis were measured by Cell Counting kit-8, Transwell chamber assay and flow cytometry, respectively. Reactive oxygen species (ROS) were detected using the dihydroethidium fluorescent probe. The mRNA expression levels of interleukin-6 and monocyte chemotactic protein-1 were measured by reverse transcription-quantitative polymerase chain reaction. Furthermore, the protein expression levels of KDM3A, mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-κB/p65, B-cell lymphoma 2 (Bcl-2)-associated X protein and Bcl-2 were evaluated by western blotting. Lentivirus transduction with KDM3A-siRNA markedly reduced the elevated expression of KDM3A induced by high insulin stimulation in VSMCs. In addition, inhibition of KDM3A significantly ameliorated insulin-induced VSMC proliferation and migration, which was accompanied by decreased ROS levels, cell apoptosis and inflammatory cytokine levels. Furthermore, KDM3A gene silencing mitigated phosphorylation of MAPKs and NF-κB/p65 activation. In conclusion, KDM3A inhibition may exert numerous protective effects on high insulin-stimulated VSMCs, and the underlying mechanisms may be partly associated with inactivation of MAPK/NF-κB signaling pathways.

LncRNA H19 ameliorates myocardial infarction‐induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A

“…Our initial studies showed that KDM3A could promote vascular neointimal hyperplasia in diabetic rats via the AGTR1 and ROCK2 signalling pathways . KDM3A inhibition could also attenuate high concentration insulin–induced vascular smooth muscle cell injury by suppressing MAPK/NF–κB pathways . In addition, our latest findings suggest that KDM3A is involved in diabetic cardiomyopathy and is a crucial factor in mediating myocardial ‘Metabolic Memory’ injury in diabetes by facilitating NF‐κB/p65 transcriptional activities.…”

“…15 KDM3A inhibition could also attenuate high concentration insulin-induced vascular smooth muscle cell injury by suppressing MAPK/NF-κB pathways. 17 In addition, our latest findings suggest that KDM3A is involved in diabetic cardiomyopathy and is a crucial factor in mediating myocardial 'Metabolic Memory' injury in diabetes by facilitating NF-κB/p65 transcriptional activities. Moreover, our unpublished research also indicated that KDM3A played an important role in myocardial ischaemia-reperfusion injury.…”

“…Numerous studies have elucidated the pathophysiological significance of KDM3A in various tumours as a poor prognostic indicator; however, its potential function in cardiovascular disease is still enigmatic. Our previous studies have provided firm evidence that KDM3A is implicated in diabetic vascular remodelling and diabetic cardiomyopathy as well as myocardial ischaemia‐reperfusion injury by regulating key signalling pathways that are involved in inflammation, apoptosis and oxidative stress . In addition, Zhang and colleagues also reported that KDM3A participated in left ventricular hypertrophy and myocardial fibrosis in response to pressure overload .…”

“…Our previous studies have provided firm evidence that KDM3A is implicated in diabetic vascular remodelling and diabetic cardiomyopathy as well as myocardial ischaemia-reperfusion injury by regulating key signalling pathways that are involved in inflammation, apoptosis and oxidative stress. 15,17 In addition, Zhang and colleagues also reported that KDM3A participated in left ventricular hypertrophy and myocardial fibrosis in response to pressure overload. 18 In the light of these considerations, we speculated that KDM3A may play a central role in the regulatory network of AMI.…”

RETRACTED ARTICLE: M2 macrophage-derived extracellular vesicles promote gastric cancer progression via a microRNA-130b-3p/MLL3/GRHL2 signaling cascade

“…A prior study has yielded similar results demonstrating that miR-130b expression was elevated in GC tissues relative to matched normal tissues, and that the upregulated miR-130b promoted cell viability and reduced death of GC cells [ 30 ]. Another study likewise showed increased miR-130b-5p expression in GC cell lines, and that GC cells with overexpressed miR-130b-5p had potentiated cell proliferation, colony formation, as well as migratory and invasive capacities [ 31 ]. High expression of other miRNAs, such as miR-130, has been observed in advanced GC tissues, which was similarly associated with risk for distant metastasis, lymph node metastasis, and poor long-term survival [ 28 ].…”