RESUMO
microRNAs (miRNAs), a subclass of noncoding short RNAs, direct cells fate decisions that are important for cell proliferation and cell lineage decisions. Adipogenic differentiation contributes greatly to the development of white adipose tissue, involving of highly organized regulation by miRNAs. In the present study, we screened and identified 78 differently expressed miRNAs of porcine BMSCs during adipogenic differentiation. Of which, the role of miR-29c in regulating the proliferation and adipogenic differentiation was proved and detailed. Specifically, over-expression miR-29c inhibits the proliferation and adipogenic differentiation of BMSCs, which were reversed upon miR-29c inhibitor. Interference of IGF1 inhibits the proliferation and adipogenic differentiation of BMSCs. Mechanistically, miR-29c regulates the proliferation and adipogenic differentiation of BMSCs by targeting IGF1 and further regulating the MAPK pathway and the PI3K-AKT-mTOR pathway, respectively. In conclusion, we highlight the important role of miR-29c in regulating proliferation and adipogenic differentiation of BMSCs.
Assuntos
Adipogenia , Diferenciação Celular , Proliferação de Células , Células-Tronco Mesenquimais , MicroRNAs , Animais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , MicroRNAs/metabolismo , Suínos , Adipogenia/genética , Células Cultivadas , Transdução de Sinais , Adipócitos/citologia , Adipócitos/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismoRESUMO
White adipose tissue (WAT) is important for regulating the whole systemic energy homeostasis. Excessive WAT accumulation further contributes to the development of obesity and obesity-related illnesses. More detailed mechanisms for WAT lipid metabolism reprogramming, however, are still elusive. Here, we report the abnormally high expression of a circular RNA (circRNA) mmu_circ_0001874 in the WAT and liver of mice with obesity. mmu_circ_0001874 interference achieved using a specific adeno-associated virus infects target tissues, down-regulating lipid accumulation in the obesity mice WAT, and liver tissues. Mechanistically, miR-24-3p directly interacts with the lipid metabolism effect of mmu_circ_0001874 and participates in adipogenesis and lipid accumulation by targeting Igf2/PI3K-AKT-mTOR axis. Moreover, mmu_circ_0001874 binds to Igf2bp2 to interact with Ucp1, up-regulating Ucp1 translation and increasing thermogenesis to decrease lipid accumulation. In conclusion, our data highlight a physiological role for circRNA in lipid metabolism reprogramming and suggest mmu_circ_0001874/miR-24-3p/Igf2/PI3K-AKT-mTOR and mmu_circ_0001874/Igf2bp2/Ucp1 axis may represent a potential mechanism for controlling lipid accumulation in obesity.
Assuntos
Metabolismo dos Lipídeos , MicroRNAs , Animais , Camundongos , Metabolismo dos Lipídeos/genética , Lipídeos , MicroRNAs/genética , Obesidade/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Circular/genética , Serina-Treonina Quinases TOR/genética , Proteína Desacopladora 1RESUMO
BACKGROUND: ANG (angiogenin) is essential for cellular adaptation to endoplasmic reticulum (ER) stress, a process closely associated with cardiovascular diseases, including atherosclerosis. We aimed to investigate the role of ANG in the progression of atherosclerosis and elucidate its underlying molecular mechanisms. METHODS: We constructed adenoassociated virus 9 ANG overexpression vectors and endothelial ANG- and ApoE (apolipoprotein E)-deficient mice to determine the effects of ANG on ER stress and atherosclerotic lesions. RNA sequencing of endothelial ANG- and ApoE-deficient mice identified ANG-dependent downregulation of ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) expression, and the direct regulation of ST3GAL5 by ANG was verified by chromatin immunoprecipitation sequencing and luciferase reporter assay results. RESULTS: Reanalysis of expression profiling datasets indicated decreased ANG levels in patients' atherosclerotic lesions, and these data were validated in aortas from ApoE-/- mice. ER stress marker and adhesion molecule levels, aortic root lesions and macrophage deposition were substantially reduced in ApoE-/- mice injected with an adenoassociated virus 9 ANG without signal peptide (ANG-ΔSP) overexpression vector compared with empty and full-length ANG overexpression vectors. Endothelial ANG deficiency significantly elevated ER stress and increased adhesion molecule expression, which aggravated atherosclerotic lesions and enhanced THP-1 monocyte adhesion to endothelial cells in vivo and in vitro, respectively. Furthermore, ANG-ΔSP overexpression significantly attenuated oxidized low-density lipoprotein-induced ER stress and THP-1 monocyte adhesion to endothelial cells, which were reversed by ST3GAL5 inhibition. CONCLUSIONS: These results suggest that endothelial intracellular ANG is a novel therapeutic against atherosclerosis and exerts atheroprotective effects via ST3GAL5-mediated ER stress suppression.
Assuntos
Aterosclerose/prevenção & controle , Estresse do Retículo Endoplasmático/fisiologia , Ribonuclease Pancreático/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Knockout , Camundongos Knockout para ApoE , Modelos Cardiovasculares , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonuclease Pancreático/deficiência , Ribonuclease Pancreático/genética , Sialiltransferases/antagonistas & inibidores , Sialiltransferases/genética , Sialiltransferases/metabolismo , Regulação para CimaRESUMO
BACKGROUND: The current study explored the effects of treadmill exercise intensity on functional recovery and hippocampal phospho-NR2B (p-NR2B) expression in cerebral ischemic rats, induced by permanent middle cerebral artery occlusion (MCAO) surgery. METHOD: Adult male Sprague-Dawley rats were randomly divided into four groups, including sham, no exercise (NE), low intensity training (LIT, v = 15 m/min), and moderate intensity training groups (MIT, v = 20 m/min). At different time points, the hippocampal expressions of p-NR2B and total NR2B were examined. In addition, neurological deficit score (NDS), body weight, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to evaluate brain infarct volume as assessments of post-stroke functional recovery. In order to investigate the effect of exercise on survival, the mortality rate was also recorded. RESULTS: The results showed that treadmill exercise significantly decreased hippocampal expression of p-NR2B but didn't change the total NR2B, compared to the NE group on the 3rd, 7th, and 14th days following MCAO surgery. The effect on changes in p-NR2B levels, body weight, and brain infarct volume were more significant in the LIT compared to the MIT group. DISCUSSION AND CONCLUSION: The current findings demonstrate that physical exercise can produce neuroprotective effects, in part by down-regulating p-NR2B expression. Furthermore, the appropriate intensity of physical exercise is critical for post-stroke rehabilitation.