Objective:Long-term diabetes can result in ventricular hypertrophic remodeling,tissue fibrosis,myocardial metabolic defection,and eventually,heart failure.Silent information regulator 6(SIRT6)exerts beneficial effects...Objective:Long-term diabetes can result in ventricular hypertrophic remodeling,tissue fibrosis,myocardial metabolic defection,and eventually,heart failure.Silent information regulator 6(SIRT6)exerts beneficial effects against cardiovascular diseases.This study is aimed to investigate whether the direct regulation of myocardial SIRT6 signaling affects cardiac performance in the case of diabetes.Meanwhile,we sought to explore the underlying mechanisms.Methods:Sprague Dawley(SD)rats were used in this experiment.Briefly,type 2 diabetic animal model was generated by streptozotocin administration along with feeding a high-fat diet.The SD rats were randomly assigned to non-diabetic group,diabetic group,diabetic injected with empty adenoviral vectors group and diabetic injected with adenoviral vectors expressing SIRT6 group(n=10,respectively).The animals were kept for another 4 weeks before sacrifice.Cardiac performance was evaluated by echocardiography.Myocardial fibrosis was determined by Masson’s trichrome staining.Myocardial SIRT6 signaling and fibrosis related molecules were measured by western blotting.Results:The diabetic myocardium exhibited markedly enhanced TGFb1-Smad2/3-induced myocardial fibrosis and reduced SIRT6 and AMP-activated protein kinase(AMPK)signaling.After 4 weeks of SIRT6 adenoviral vector infection,myocardial tissues exhibited markedly enhanced SIRT6 and AMPK signaling.Additionally,myocardial fibrosis and TGFb1-Smad2/3 signaling were both attenuated in the diabetic injected with adenoviral vectors expressing SIRT6 group.Conclusions:SIRT6-AMPK signaling suppressed the progression of tissue fibrosis in diabetes mellitus rats by inhibiting TGFb1 and its downstream effector Smad2/3.SIRT6 might serve as an alternative therapeutic target for diabetes-related cardiovascular diseases.展开更多
目的基于沉默信息调节因子1(silent information regulator 1,SIRT1)/高迁移率族蛋白B1(high mobility group protein B1,HMGB1)/核转录因子-κB(nuclear transcription factor-κB,NF-κB)信号轴探讨丹参绞股蓝茶对四氯化碳(carbon tet...目的基于沉默信息调节因子1(silent information regulator 1,SIRT1)/高迁移率族蛋白B1(high mobility group protein B1,HMGB1)/核转录因子-κB(nuclear transcription factor-κB,NF-κB)信号轴探讨丹参绞股蓝茶对四氯化碳(carbon tetrachloride,CCl4)所致小鼠急性肝损伤肝细胞炎症凋亡反应的抑制作用和机制研究。方法C57BL/6小鼠随机分为正常组、模型组、白藜芦醇组、丹参绞股蓝茶低、中、高剂量组、阳性药组,连续灌胃给药14 d。采用腹腔注射0.5%CCl4橄榄油溶液(5 mL/kg)的方法建立小鼠急性肝损伤模型。生化法检测小鼠血清中丙氨酸转移酶(alanine transferase,ALT)、天冬氨酸转移酶(aspartate transferase,AST)、乳酸脱氢酶(lactate dehydrogenase,LDH)及肝组织羟脯氨酸(hydroxyproline,Hyp)、丙二醛(malonaldehyde,MDA)和超氧化物歧化酶(superoxide dismutase,SOD)水平;酶联免疫吸附法检测血清炎性因子肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-6(interleukin-6,IL-6)和白细胞介素-1β(interleukin-1β,IL-1β)水平;苏木素-伊红(HE)染色和TUNEL染色检测肝组织病理形态结构和肝细胞凋亡情况;Western Blot检测SIRT1、HMGB1和NF-κB蛋白表达。结果与正常组比较,模型组小鼠血清ALT、AST、LDH水平和肝组织Hyp活性显著升高,以及肝组织中MDA和SOD活性明显降低,血清炎性因子TNF-α、IL-6和IL-1β水平显著升高(P<0.05或P<0.01),肝组织存在明显的病理损伤以及肝细胞凋亡情况,肝组织中SIRT1蛋白的表达明显降低,HMGB1和NF-κB蛋白的表达升高;与模型组比较,丹参绞股蓝茶高剂量组和白藜芦醇组小鼠血清肝功能指标ALT、AST、LDH水平和肝组织Hyp活性显著降低,以及肝组织中MDA和SOD活性明显增加,血清炎性因子TNF-α、IL-6和IL-1β水平显著降低,肝组织的病理损伤以及肝细胞凋亡情况得到明显改善,肝组织中SIRT1蛋白表达增加,HMGB1和NF-κB蛋白的表达降低(P<0.05或P<0.01)。结论丹参绞股蓝茶能有效保护急性肝损伤,其作用机制可能与调控SIRT1/HMGB1/NF-κB信号通路,减轻肝细胞炎性凋亡有关。展开更多
目的探讨利拉鲁肽通过沉默信息调节因子1(silent information regulator 1,SIRT1)/腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)通路改善小鼠肝脏脂质变性的机制。方法将24只健康雄性6周龄C57BL/6J小鼠...目的探讨利拉鲁肽通过沉默信息调节因子1(silent information regulator 1,SIRT1)/腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)通路改善小鼠肝脏脂质变性的机制。方法将24只健康雄性6周龄C57BL/6J小鼠随机分为对照组、模型组、模型+利拉鲁肽组、模型+SIRT1组、模型+SIRT1+利拉鲁肽组、模型+SIRT1-NC组,每组4只。对照组普通饲料饲养,予以等容积生理盐水皮下注射,模型组高脂饲养12周建立代谢相关脂肪性肝病(metabolic dysfunction-associated fatty liver disease,MAFLD)模型,之后3周尾静脉注射SIRT1干扰慢病毒及利拉鲁肽。检测各组小鼠血清甘油三酯和丙氨酸氨基转移酶(alanine aminotransferase,ALT)水平,采用HE染色和油红O染色观察肝组织病理,采用实时荧光定量RT-PCR检测AMPK、SIRT1、肝激酶B1(liver kinase B1,LKB1)和去乙酰化固醇调节元件结合蛋白(sterol regulatory element binding protein-1c,SREBP-1c)基因表达水平,采用Western blot检测蛋白表达水平。结果利拉鲁肽可降低高脂喂养的C57BL/6J小鼠体质量、肝湿重、血清甘油三酯及ALT水平,油红O染色可见肝细胞脂滴减少。与模型组相比,模型+利拉鲁肽组SIRT1(0.212±0.110比0.076±0.010)、AMPK(0.518±0.051比0.248±0.023)、LKB1(1.023±0.039比0.576±0.029)基因表达量和AMPK(0.212±0.026比0.100±0.006)、LKB1(0.413±0.016比0.221±0.015)蛋白表达水平均上调,而SREBP-1c基因(0.727±0.249比9.007±1.530)和蛋白(0.187±0.008比0.824±0.114)表达水平均下调(P均<0.05)。与模型组相比,模型+SIRT1组SIRT1(0.029±0.003比0.076±0.010)、AMPK(0.105±0.013比0.248±0.023)、LKB1(0.333±0.106比0.576±0.029)基因表达量均下调(P均<0.05)。与模型+SIRT1组相比,模型+SIRT1+利拉鲁肽组LKB1(0.945±0.110比0.333±0.106;0.380±0.004比0.145±0.014)、AMPK(0.319±0.051比0.105±0.013;0.181±0.039比0.051±0.012)基因表达量和蛋白表达量均上调,而SREBP-1c基因表达量(4.239±0.554比12.740±0.976)下调(P均<0.05)。结论利拉鲁肽改善C57BL/6J小鼠肝脏脂毒性可能通过直接上调SIRT1/AMPK通路信号分子基因和蛋白表达水平,或间接激活LKB1并增强AMPK基因和蛋白表达、拮抗SREBP-1c基因和蛋白表达,从而降低脂质合成相关分子水平,而干扰SIRT1表达削弱了利拉鲁肽上调SIRT1/AMPK通路改善肝脏脂肪变性的作用。展开更多
Heart failure(HF)is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden.In addition to cardiac myocyte oxidative stress and apopto...Heart failure(HF)is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden.In addition to cardiac myocyte oxidative stress and apoptosis,which are considered mechanisms for the development of HF,alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF.Silent information regulator 1(Sirt1)and adenosine monophosphate-activated protein kinase(AMPK)are nicotinamide adenine dinucleotide(NAD+)-dependent deacetylases and phosphorylated kinases,respectively.They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),protein 38 mitogen-activated protein kinase(p38 MAPK),peroxisome proliferator-activated receptors(PPARs),and mammalian target of rapamycin(mTOR).We summarized the synergistic effects of Sirt1 and AMPK in the heart,and listed the traditional Chinese medicine(TCM)that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway,to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases(CVDs).展开更多
As a non-communicable disease,cardiovascular disorders have become the lea-ding cause of death for men and women.Of additional concern is that cardio-vascular disease is linked to chronic comorbidity disorders that in...As a non-communicable disease,cardiovascular disorders have become the lea-ding cause of death for men and women.Of additional concern is that cardio-vascular disease is linked to chronic comorbidity disorders that include nonal-coholic fatty liver disease(NAFLD).NAFLD,also termed metabolic-dysfunction-associated steatotic liver disease,is the greatest cause of liver disease throughout the world,increasing in prevalence concurrently with diabetes mellitus(DM),and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fi-brosis.Individuals with metabolic disorders,such as DM,are more than two times likely to experience cardiac disease,stroke,and liver disease that includes NAFLD when compared individuals without metabolic disorders.Interestingly,cardiovascular disorders and NAFLD share a common underlying cellular me-chanism for disease pathology,namely the silent mating type information regu-lation 2 homolog 1(SIRT1;Saccharomyces cerevisiae).SIRT1,a histone deacetylase,is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues,including trophic factors such as erythropoietin,stem cells,and AMP-activated protein kinase.Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients,but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens.展开更多
基金supported by grants from the National Natural Science Foundation of China(81700264)Postdoctoral Science Foundation Grant of China(2018M643839)the Natural Science Foundation of Liaoning Province(2020-MS-036).
文摘Objective:Long-term diabetes can result in ventricular hypertrophic remodeling,tissue fibrosis,myocardial metabolic defection,and eventually,heart failure.Silent information regulator 6(SIRT6)exerts beneficial effects against cardiovascular diseases.This study is aimed to investigate whether the direct regulation of myocardial SIRT6 signaling affects cardiac performance in the case of diabetes.Meanwhile,we sought to explore the underlying mechanisms.Methods:Sprague Dawley(SD)rats were used in this experiment.Briefly,type 2 diabetic animal model was generated by streptozotocin administration along with feeding a high-fat diet.The SD rats were randomly assigned to non-diabetic group,diabetic group,diabetic injected with empty adenoviral vectors group and diabetic injected with adenoviral vectors expressing SIRT6 group(n=10,respectively).The animals were kept for another 4 weeks before sacrifice.Cardiac performance was evaluated by echocardiography.Myocardial fibrosis was determined by Masson’s trichrome staining.Myocardial SIRT6 signaling and fibrosis related molecules were measured by western blotting.Results:The diabetic myocardium exhibited markedly enhanced TGFb1-Smad2/3-induced myocardial fibrosis and reduced SIRT6 and AMP-activated protein kinase(AMPK)signaling.After 4 weeks of SIRT6 adenoviral vector infection,myocardial tissues exhibited markedly enhanced SIRT6 and AMPK signaling.Additionally,myocardial fibrosis and TGFb1-Smad2/3 signaling were both attenuated in the diabetic injected with adenoviral vectors expressing SIRT6 group.Conclusions:SIRT6-AMPK signaling suppressed the progression of tissue fibrosis in diabetes mellitus rats by inhibiting TGFb1 and its downstream effector Smad2/3.SIRT6 might serve as an alternative therapeutic target for diabetes-related cardiovascular diseases.
基金supported by the Natural Science Foundation of China(Grant No.:82130113)the“Xinglin Scholars”Research Promotion Program of Chengdu University of Traditional Chinese Medicine(Program No.:ZDZX2022005)+1 种基金the China Postdoctoral Science Foundation(Grant No.:2021MD703800)the Science Foundation for Youths of Science&Technology Department of Sichuan Province(Grant No.:2022NSFSC1449).
文摘Heart failure(HF)is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden.In addition to cardiac myocyte oxidative stress and apoptosis,which are considered mechanisms for the development of HF,alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF.Silent information regulator 1(Sirt1)and adenosine monophosphate-activated protein kinase(AMPK)are nicotinamide adenine dinucleotide(NAD+)-dependent deacetylases and phosphorylated kinases,respectively.They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α),protein 38 mitogen-activated protein kinase(p38 MAPK),peroxisome proliferator-activated receptors(PPARs),and mammalian target of rapamycin(mTOR).We summarized the synergistic effects of Sirt1 and AMPK in the heart,and listed the traditional Chinese medicine(TCM)that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway,to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases(CVDs).
基金Supported by American Diabetes AssociationAmerican Heart Association+4 种基金NIH NIEHSNIH NIANIH NINDSNS053956NIH ARRA.
文摘As a non-communicable disease,cardiovascular disorders have become the lea-ding cause of death for men and women.Of additional concern is that cardio-vascular disease is linked to chronic comorbidity disorders that include nonal-coholic fatty liver disease(NAFLD).NAFLD,also termed metabolic-dysfunction-associated steatotic liver disease,is the greatest cause of liver disease throughout the world,increasing in prevalence concurrently with diabetes mellitus(DM),and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fi-brosis.Individuals with metabolic disorders,such as DM,are more than two times likely to experience cardiac disease,stroke,and liver disease that includes NAFLD when compared individuals without metabolic disorders.Interestingly,cardiovascular disorders and NAFLD share a common underlying cellular me-chanism for disease pathology,namely the silent mating type information regu-lation 2 homolog 1(SIRT1;Saccharomyces cerevisiae).SIRT1,a histone deacetylase,is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues,including trophic factors such as erythropoietin,stem cells,and AMP-activated protein kinase.Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients,but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens.
