The HOX transcript antisense RNA (HOTAIR) long noncoding RNA (lncRNA), a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, to date, the significance of HOTAIR in diabetic cardiomyopathy (DCM) has never been investigated. The current study was designed to determine whether DCM can be regulated by HOTAIR and to elucidate the related mechanism. In vivo, streptozotocin (STZ) was injected intraperitoneally to induce type 1 diabetes in mice. Cardiomyocyte specific HOTAIR overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. In vitro, H9c2 were used to explore the potential molecular mechanism of HOTAIR in the regulation of high-glucose-induced cardiomyocyte injury. Luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the relationship between HOTAIR, microRNA-34a (miR-34a), and Sirtuin 1 (SIRT1). HOTAIR expression was significantly decreased in diabetic mice hearts. Knockdown of HOTAIR in high glucose-induced H9c2 resulted in increased oxidative injury, inflammation, and apoptosis in vitro. Cardiomyocyte-specific overexpression of HOTAIR improved cardiac function, decreased oxidative stress and inflammation, and attenuated myocyte death in mice treated with STZ. Mechanistically, the expression of SIRT1/forkhead box protein O1 was significantly increased in the HOTAIR-overexpressing hearts compared with the control hearts treated with STZ. Moreover, we found HOTAIR functioned as a molecular sponge of miR-34a in H9c2 and SIRT1 was identified as a target of miR-34a. Furthermore, the protective effects of HOTAIR on DCM was abolished in SIRT1 deficiency mice in vivo. HOTAIR protected against DCM via activation of the SIRT1 expression by sponging miR-34a.
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFDinduced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogenactivated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD. (Hepatology 2019;70:1099-1118). SEE EDITORIAL ON PAGE 1091N onalcoholic fatty liver disease (NAFLD) is the most common diffuse liver disease and is characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. (1) The prevalence of NAFLD increases worryingly with obesity and other diseases of metabolic syndrome (MS) and is expected to be the leading cause of liver failure in the future. (2) Accumulating studies show that NAFLD not only is linked to an increased risk of liver-related mortality or morbidity
Diabetes contributes to cardiovascular complications and the pathogenesis of cardiac remodeling that can lead to heart failure. We aimed to evaluate the functional role of LAZ3 in diabetic cardiomyopathy (DCM). Streptozotocin (STZ) was used to induce a diabetic mouse model. Three months after induction, the mice were subjected to retro-orbital venous plexus injection of adeno-associated virus 9 (AAV9) that overexpressed LAZ3. Six weeks after the infection, mouse hearts were removed to assess the degree of cardiac remodeling. LAZ3 was down-regulated in the diabetic mouse hearts and high glucose stimulated cardiomyocytes. Knock-down of LAZ3 in cardiomyocytes with LAZ3 siRNA reduced cell viability, increased the inflammatory response and induced oxidative stress and cell apoptosis. Overexpression of LAZ3 by infection with adeno-associated virus (AAV9)-LAZ3 protected against an inflammatory response, oxidative stress and cell apoptosis in both a high glucose stimulated in vitro study and diabetic mouse hearts. We found that LAZ3 increased the activation of PPARa, which increased PGC-1a activation and subsequently augmented NRF2 expression and nuclear translocation. This outcome was confirmed by NRF2 siRNA and a PPARa activator, since NRF2 siRNA abrogated the protective effects of LAZ3 overexpression, while the PPARa activator reversed the deteriorating phenotype of LAZ3 knock-down in both the in vitro and vivo study. Furthermore, LAZ3 decreased miR-21 expression, which resulted in PPARa activation, NRF2 expression and nuclear translocation. In conclusion, LAZ3 protects against cardiac remodeling in DCM by decreasing miR-21, thus regulating PPARa/NRF2 signaling.
Background/Aims: Vascular smooth muscle cell (VSMC) hyperplasia plays important roles in the pathogenesis of many vascular diseases, such as atherosclerosis and restenosis. Many microRNAs (miRs) have recently been reported to regulate the proliferation and migration of VSMC. In the current study, we aimed to explore the function of miR-93 in VSMCs and its molecular mechanism.Methods: First, qRT-PCR and immunofluorescence assays were performed to determine miR-93 expression in rat VSMCs following carotid artery injury in vivo and platelet-derived growth factor-BB (PDGF-BB) stimulation in vitro. Next, the biological role of miR-93 in rat VSMC proliferation and migration was examined in vivo and vitro. EdU incorporation assay and MTT assay for measuring cell proliferation, Transwell cell invasion assay and Cell scratch wound assay for measuring cell migration. Then, the targets of miR-93 were identified. Finally, the expression levels of proteins in the Raf-ERK1/2 pathway were measured by western blot.Results: MiR-93 was upregulated in rat VSMCs following carotid artery injury in vivo. Similar results were observed in ex vivo cultured VSMCs after PDGF-BB treatment. MiR-93 inhibition suppressed neointimal formation after carotid artery injury. Moreover, our results demonstrated that a miR-93 inhibitor suppressed the PDGF-BB induced proliferation and migration of in VSMC. This inhibitor also decreased the expression levels of MMP2 and cyclin D1. Mechanistically, we discovered that mitofusin 2(Mfn2) is a direct target of miR-93. Furthermore, an analysis of the signaling events revealed that miR-93-mediated VSMC proliferation and migration occurred via the Raf-ERK1/2 pathway.Conclusions: Our findings suggest that miR-93 promotes VSMCs proliferation and migration by targeting Mfn2. MiR-93 may be a new target for treating in-stent restenosis.
Melatonin has been shown to inhibit myocardial infarction-induced apoptosis, its function in heart failure with preserved ejection fraction (HFpEF) has not been investigated. This study aimed to investigate whether melatonin attenuates obesity-related HFpEF. Male mice were fed a high-fat diet (HFD) from weaning to 6 months of age to induce HFpEF. The mice were orally administered melatonin (50 mg/kg) by 3 weeks. Diastolic function was significantly improved by melatonin supplementation in mice fed an HFD. Melatonin attenuated obesity-induced myocardial oxidative stress and apoptosis and promoted the secretion of C1q/tumour necrosis factor-related protein 3 (CTRP3) by adipose tissue. And depletion of circulating CTRP3 largely abolished melatonin-mediated cardio-protection. Melatonin-mediated secretion of adipocyte-derived CTRP3 activated NF-E2-related factor 2 (Nrf2), which were largely abrogated by knocking down CTRP3 in adipocytes or Nrf2 in cardiomyocytes. Nrf2 activation was mediated by miR-200a, and a miR-200a antagomir offset the effects of melatonin-conditioned medium on Nrf2 expression. Our results indicate that melatonin can be used to treat and prevent obesity-related HFpEF.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.