Mutations in mitochondrial DNA, especially in mitochondrial tRNA (mt-tRNA) genes, are the important causes for maternally inherited hypertension. In this study, we reported the clinical, genetic, and molecular characterization of a Han Chinese family with hypertension. Most strikingly, this family exhibited a high penetrance and expressivity of hypertension. Sequence analysis of the complete mt-tRNA genes showed the presence of tRNA A4435G and tRNA C5601T mutations. The A4435G had already been reported as a pathogenic mutation associated with hypertension; in addition, the C5601T mutation, which was located at the highly conserved nucleotide of T arm of tRNA, created a novel Watson-Crick base pairing and may result in failure of tRNA metabolism. Moreover, bioinformatics analysis indicated that the C5601T mutation altered the secondary structure of tRNA. Thus, the mitochondrial dysfunction, caused by the A4435G mutation, may be worsened by the C5601T mutation. Taken together, our data indicated that the co-occurrence of the A4435G and C5601T mutations may account for the high penetrance and expressivity of hypertension in this family. Therefore, our study provided novel insight into the pathophysiology of maternally inherited hypertension.
Acute kidney injury (AKI) is a clinical syndrome caused by various reasons that results in the rapid decline of renal function in a short period of time. Severe AKI can lead to multiple organ dysfunction syndrome. Circular RNA HIPK3 (circHIPK3) derived from the HIPK3 gene is involved in multiple inflammatory processes. The present research was performed to explore the function of circHIPK3 on AKI. The AKI model was established by ischemia/reperfusion (I/R) in C57BL/6 mice or hypoxia/reoxygenation (H/R) in HK-2 cells. The function and mechanism of circHIPK3 on AKI were explored via biochemical index measurement; hematoxylin and eosin (HE) staining; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); flow cytometry; enzyme-linked immunosorbent assay (ELISA); western blot; quantitative real-time polymerase chain reaction (RT-qPCR); detection of reactive oxygen species (ROS) and adenosine triphosphate (ATP); and luciferase reporter assays. circHIPK3 was upregulated in kidney tissues of I/R-induced mice and in H/R-treated HK-2 cells, while the microRNA- (miR-) 93-5p level was decreased in H/R-stimulated HK-2 cells. Furthermore, circHIPK3 silencing or miR-93-5p overexpression could reduce the level of proinflammatory factors and oxidative stress and recover the cell viability in H/R-stimulated HK-2 cells. Meanwhile, the luciferase assay showed that Krüppel-like transcription factor 9 (KLF9) was the downstream target of miR-93-5p. Forced expression of KLF9 blocked the function of miR-93-5p on H/R-treated HK-2 cells. Knockdown of circHIPK3 improved the renal function and reduced the apoptosis level in vivo. In conclusion, circHIPK3 knockdown alleviated oxidative stress and apoptosis and inhibited inflammation in AKI via miR-93-5p-mediated downregulation of the KLF9 signal pathway.
Background: Nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the progression of many cancers; however, the role and mechanisms underlying NEAT1 in abdominal aortic aneurysm (AAA) remain unclear.
Methods and Results:The expression of NEAT1, miR-30d-5p and A disintegrin and metalloprotease 10 (ADAM10) was measured by qRT-PCR and western blot. Functional experiments were conducted by using a CCK-8 assay, EDU assay, flow cytometry, western blot, ELISA, and commercial kits. The target relation was confirmed by dual-luciferase reporter assay and the RIP assay. It was then found that NEAT1 was upregulated in peripheral blood of AAA patients ~3.46-fold, smooth muscle cells (SMCs) isolated from AAA tissues ~2.6-fold and in a hydrogen peroxide (H2O2)-induced injury model of human vascular SMC (HVSMCs) ~2.0-and 3.9-fold at 50 µmol/L and 200 µmol/L H2O2 treatment, respectively. NEAT1 deletion attenuated H2O2-induced cell proliferation promotion (40.0% vs. 74.3%), apoptosis inhibition (25.0% vs. 13.5%), and reduction of inflammatory response and oxidative stress in HVSMCs. Mechanistically, NEAT1 targeted miR-30d-5p to prevent the degradation of its target, ADAM10, in HVSMCs. Further rescue experiments suggested miR-30d-5p inhibition mitigated the effects of NEAT1 deletion on H2O2-induced HVSMCs. Moreover, ADAM10 overexpression counteracted the inhibitory functions of miR-30d-5p on H2O2-evoked HVSMC injury.Conclusions: NEAT1 promoted H2O2-induced HVSMC injury by inducing cell apoptosis, inflammation and oxidative stress through miR-30d-5p/ADAM10 axis, indicating the possible involvement of NEAT1 in the pathogenesis of AAA.
Background: Stroke is a severe complication of patients with type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR). Our aim is to identify predictors of stroke after TEVAR.Methods: From February 2016 to February 2019, 445 patients with TBAD who underwent TEVAR were retrospectively analyzed. Univariate and multivariate analyses were performed to identify predictors of stroke after TEVAR.Results: The total incidence of stroke was 11.5%, with transient neurological dysfunction (TND) of 10.6% and permanent neurological dysfunction (PND) of 0.9%. The average age of the patients was 53.0 ± 3.2 years, and the male/female ratio was 1.17. Univariate analysis suggested that age, body mass index (BMI), diabetes mellitus, chronic obstructive pulmonary disease (COPD), the urgency of repair, type of anesthesia, and left subclavian artery (LSCA) processing were potential risks factors of stroke after TEVAR. Multiple logistic regression identified that LSCA coverage (OR = 5.920, 95% CI: 2.077–16.878), diabetes mellitus (OR = 3.036, 95% CI: 1.025–8.995), and general anesthesia (OR = 2.498, 95% CI: 1.002–6.229) were independent predictors of stroke after TEVAR.Conclusions: Left subclavian artery (LSCA) coverage, diabetes mellitus, and general anesthesia were independent risk factors of stroke after TEVAR for TBAD.
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