DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We genera...DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury.Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart failure.Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions.Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart failure.We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure.These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.展开更多
Background:Leukemia inhibitory factor(LIF)has been reported to possess various pharmacological effects,including displaying vascular and neuroprotective properties,during retinal disease.The aim of this study was to i...Background:Leukemia inhibitory factor(LIF)has been reported to possess various pharmacological effects,including displaying vascular and neuroprotective properties,during retinal disease.The aim of this study was to investigate the vascular and structural changes in the retina of diabetic mice and to explore whether LIF prevents experimental diabetes-induced retinal injury in the early stages.Methods:Diabetes was induced in C57BI/6J mice with streptozotocin(STZ)injections.Successful diabetic animal models were randomly separated into two groups:the diabetic group(n=15)and the LIF-treated group(n=15).Normal C57BL/6 mice served as the normal control group(n=14).Recombinant human LIF was intravitreally injected 8 weeks after the diabetic model was successfully established.Retinas were collected and evaluated using histological and immunohistochemical techniques,and flat-mounted retinas and Western blotting were performed at 18 weeks after the induction of diabetes and 2 days after the intravitreal injection of LIF.The analysis of variance test were used.Results:Histological analysis showed that there were fewer retinal ganglion cells(RGCs)and the inner nuclear layer(INL)became thinner in the diabetic model group(RGC 21.8±4.0 and INL 120.2±4.6μm)compared with the normal control group(RGC 29.0±6.7,t=-3.02,P=0.007;INL 150.7±10.6 lain,t=-8.88,P〈0.001,respectively).After LIF treatment,the number of RGCs(26.9±5.3)was significantly increased(t=3.39,P=0.030)and the INL(134.5±14.2 lain)was thicker compared to the diabetic group(t-2.75,P=0.013).In the anti-Brn-3a-labeled retinas,the number of RGCs in the LIF-treated group(3926.0±143.9)was obviously increased compared to the diabetic group(3507.7±286.1,t=2.38,P=0.030),while no significance was found between the LIF-treated group and the control group(4188.3±114.7,t=-2.47,P-0.069).Flat-mounted retinas demonstrated that a disorganized,dense distribution of the vessel was prominent in the diabetic model group.Vessel distribution in the LIF-treated mouse group was typical and the thickness was uniform.The levels of phosphosignal transducer and activator of transcription 3 activation were obviously higher in the LIF-injected retinas than those in the diabetic control group(t=3.85,P=0.019)and the normal control(t=-3.20,P-0.019).Conclusion:The present study provides evidence that LIF treatment protects the integrity of the vasculature and prevents retinal injury in the early stages of diabetic retinopathy in STZ-induced diabetic models.展开更多
基金supported by grants from the National Key R&D Program of China(2021YFE0114200,2018YFC2000100)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-050)+4 种基金the Project funded by China Postdoctoral Science Foundation(2023M732704)the National Natural Science Foundation of China(81770228,82370584,81470427 and U23A20470)the Beijing Natural Science Foundation(7232141,7212086)the Beijing Hospital Clinical Research 121 Project(121-2016004)the National High Level Hospital Clinical Research Funding(BJ-2021-199,BJ-2023-156,BJ-2019-159).
文摘DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury.Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart failure.Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions.Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart failure.We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure.These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.
基金supported by grants from the ScientificResearch Common Program of Beijing Municipal Commission of Education(No.KM201410025017)the High-level Technical Personnel Training Program of BeijingMunicipal Health System(No.2014-3-007).
文摘Background:Leukemia inhibitory factor(LIF)has been reported to possess various pharmacological effects,including displaying vascular and neuroprotective properties,during retinal disease.The aim of this study was to investigate the vascular and structural changes in the retina of diabetic mice and to explore whether LIF prevents experimental diabetes-induced retinal injury in the early stages.Methods:Diabetes was induced in C57BI/6J mice with streptozotocin(STZ)injections.Successful diabetic animal models were randomly separated into two groups:the diabetic group(n=15)and the LIF-treated group(n=15).Normal C57BL/6 mice served as the normal control group(n=14).Recombinant human LIF was intravitreally injected 8 weeks after the diabetic model was successfully established.Retinas were collected and evaluated using histological and immunohistochemical techniques,and flat-mounted retinas and Western blotting were performed at 18 weeks after the induction of diabetes and 2 days after the intravitreal injection of LIF.The analysis of variance test were used.Results:Histological analysis showed that there were fewer retinal ganglion cells(RGCs)and the inner nuclear layer(INL)became thinner in the diabetic model group(RGC 21.8±4.0 and INL 120.2±4.6μm)compared with the normal control group(RGC 29.0±6.7,t=-3.02,P=0.007;INL 150.7±10.6 lain,t=-8.88,P〈0.001,respectively).After LIF treatment,the number of RGCs(26.9±5.3)was significantly increased(t=3.39,P=0.030)and the INL(134.5±14.2 lain)was thicker compared to the diabetic group(t-2.75,P=0.013).In the anti-Brn-3a-labeled retinas,the number of RGCs in the LIF-treated group(3926.0±143.9)was obviously increased compared to the diabetic group(3507.7±286.1,t=2.38,P=0.030),while no significance was found between the LIF-treated group and the control group(4188.3±114.7,t=-2.47,P-0.069).Flat-mounted retinas demonstrated that a disorganized,dense distribution of the vessel was prominent in the diabetic model group.Vessel distribution in the LIF-treated mouse group was typical and the thickness was uniform.The levels of phosphosignal transducer and activator of transcription 3 activation were obviously higher in the LIF-injected retinas than those in the diabetic control group(t=3.85,P=0.019)and the normal control(t=-3.20,P-0.019).Conclusion:The present study provides evidence that LIF treatment protects the integrity of the vasculature and prevents retinal injury in the early stages of diabetic retinopathy in STZ-induced diabetic models.
