Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have ...Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated.Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection.However,standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective,high-quality animal studies using exercise to prevent and treat cardiovascular diseases.In our review,we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training,emphasizing the appropriate measurements and analysis in these chronic exercise models.We also provide recommendations for optimal design of animal exercise studies in cardiovascular research,including the choice of exercise models,control of exercise protocols,exercise at different stages of disease,and other considerations,such as age,sex,and genetic background.We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.展开更多
Cardiovascular diseases cause significant morbidity and mortality worldwide.Engineered cardiac organoids are being developed and used to replicate cardiac tissues supporting cardiac morphogenesis and development.These...Cardiovascular diseases cause significant morbidity and mortality worldwide.Engineered cardiac organoids are being developed and used to replicate cardiac tissues supporting cardiac morphogenesis and development.These organoids have applications in drug screening,cardiac disease models and regenerative medicine.Therefore,a thorough understanding of cardiac organoids and a comprehensive overview of their development are essential for cardiac tissue engineering.This review summarises different types of cardiac organoids used to explore cardiac function,including those based on co-culture,aggregation,scaffolds,and geometries.The self-assembly of monolayers,multilayers and aggravated cardiomyocytes forms biofunctional cell aggregates in cardiac organoids,elucidating the formation mechanism of scaffold-free cardiac organoids.In contrast,scaffolds such as decellularised extracellular matrices,three-dimensional hydrogels and bioprinting techniques provide a supportive framework for cardiac organoids,playing a crucial role in cardiac development.Different geometries are engineered to create cardiac organoids,facilitating the investigation of intrinsic communication between cardiac organoids and biomechanical pathways.Additionally,this review emphasises the relationship between cardiac organoids and the cardiac system,and evaluates their clinical applications.This review aims to provide valuable insights into the study of three-dimensional cardiac organoids and their clinical potential.展开更多
Exercise training is beneficial to the cardiovascular system. MicroRNAs (miRNAs, miRs) are a class of conserved non-coding RNAs and play a wide-ranging role in the regulation of eukaryotic gene expression. Exercise ...Exercise training is beneficial to the cardiovascular system. MicroRNAs (miRNAs, miRs) are a class of conserved non-coding RNAs and play a wide-ranging role in the regulation of eukaryotic gene expression. Exercise training alters the expression levels of large amounts ofmiRNAs in the heart. In addition, circulating miRNAs appear to be regulated by exercise training. In this review, we will summarize recent advances in the regulation of miRNAs during physical exercise intervention in various cardiovascular diseases, including pathologic cardiac hypertrophy, myocardial fibrosis, ischemia-reperfusion injury, myocardial infarction, and heart failure. The regulatory role of circulating miRNAs after exercise training was also reviewed. In conclusion, miRNAs might be a valuable target for treatment of cardiovascular diseases and have great potential as biomarkers for assessment of physical performance.2018 Published by Elsevier B.V.on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/).展开更多
Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocy...Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.展开更多
Cardiovascular disease(CVD)is a major cause of mortality and morbidity worldwide.In China,it is estimated that 330 million people are CVD patients.With the rapid aging of populations around the world,the number of CVD...Cardiovascular disease(CVD)is a major cause of mortality and morbidity worldwide.In China,it is estimated that 330 million people are CVD patients.With the rapid aging of populations around the world,the number of CVD patients and death due to CVD are continuously rising.1 Exercise and physical activity have been recognized as economical and effective ways to enhance cardiovascular health and reduce CVD.Pathways mediating the cardiovascular benefits of exercise are promising therapeutic targets for CVD.展开更多
Cardiac substrate utilization remains a critical focus for the research community.1 Research has acknowledged the role of metabolic flexibility in the development and progression of cardiac dysfunction during a variet...Cardiac substrate utilization remains a critical focus for the research community.1 Research has acknowledged the role of metabolic flexibility in the development and progression of cardiac dysfunction during a variety of diseases and conditions.2,3 Under resting basal conditions,the heart relies on fatty acid metabolism as the primary energy source with glucose,lactate,ketone bodies,pyruvate,acetate,and branched-chain amino acids contributing as substrates depending on substrate availability,hormonal status,and myocardial conditioning.4 In addition to pathological states,physiological states,such as acute exercise,induce dynamic changes in substrate metabolism,including nearly a 10-fold increase in myocardial oxygen consumption.3,5 To meet the increased demand for energy during and after a bout of exercise,the heart muscle must exhibit metabolic flexibility and selectively utilize different substrates for adenosine triphosphate production.Moreover,metabolic substrate adaptations depend on the frequency,intensity,duration,and mode of exercise while multiple metabolic fluxes,such as the use,storage and mobilization of substrates must be coordinated to maintain energy homeostasis.1,2 Although many different processes of exercise-induced regulation and metabolic remodeling have been identified,35 the effect of exercise on cellular metabolism and the landscape of metabolic pathway regulation in response to both acute exercise and chronic exercise training remain unclear.展开更多
Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative an...Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.展开更多
RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RN...RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RNAs(ncRNAs)are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions.Similar to mRNAs,m^(6)A deposition is observed in ncRNAs.Studying RNA m^(6)A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications.In this review,we summarized the recent research findings regarding the mutual regulation between RNA m^(6)A modification and ncRNAs(with a specific focus on microRNAs,long non-coding RNAs,and circular RNAs)and their functions.We also discussed the challenges of m^(6)A-containing ncRNAs and RNA m^(6)A as therapeutic targets in human diseases and their future perspective in translational roles.展开更多
Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle at...Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.展开更多
Cardiovascular disease is the leading cause of human death worldwide. Autophagy is an evolutionarily conserved degradation pathway,which is a highly conserved cellular degradation process in which lysosomes decompose ...Cardiovascular disease is the leading cause of human death worldwide. Autophagy is an evolutionarily conserved degradation pathway,which is a highly conserved cellular degradation process in which lysosomes decompose their own organelles and recycle the resulting macromolecules.Autophagy is critical in maintaining cardiovascular homeostasis and function, and excessive or insufficient autophagy or autophagic flux can lead to cardiovascular disease. Enormous evidence indicates that exercise training plays a beneficial role in the prevention and treatment of cardiovascular diseases. The regulation of autophagy during exercise is a bidirectional process. For cardiovascular disease caused by either insufficient or excessive autophagy, exercise training restores normal autophagy function and delays the progression of cardiovascular disease.An in-depth exploration and discussion of exercise-mediated regulation of autophagy in the cardiovascular system can broaden our view about the prevention of various autophagy-related diseases through exercise training. In this article, we review autophagy and its related signaling pathways,as well as autophagy-dependent beneficial effects of exercise in cardiovascular system.展开更多
Cardiovascular disease is one of the leading causes of mortality worldwide.Recent studies have shown that circular RNAs(circRNAs)have emerged as important players in the prevention and treatment of cardiovascular dise...Cardiovascular disease is one of the leading causes of mortality worldwide.Recent studies have shown that circular RNAs(circRNAs)have emerged as important players in the prevention and treatment of cardiovascular diseases.circRNAs are a class of endogenous noncoding RNAs that are generated by back-splicing and are involved in many pathophysiological processes.In this review,we outline the current research progress on the regulatory roles of circRNAs in cardiovascular diseases.Further,new technologies and methods available for identifying,validating,synthesizing,and analyzing circRNAs,as well as their applications in therapeutics,are highlighted here.Moreover,we summarize the increasing insights into the potential use of circRNAs as circulating diagnostic and prognostic biomarkers.Finally,we discuss the prospects and challenges of circRNA therapeutic applications for cardiovascular disease therapy,with a particular focus on developing circRNA synthesis and engineering delivery systems.展开更多
Objective Epidemiological studies reveal that exposure to fine particulate matter(aerodynamic diameter≤2.5μm,PM_(2.5))increases the morbidity and mortality of respiratory diseases.Emerging evidence suggests that hum...Objective Epidemiological studies reveal that exposure to fine particulate matter(aerodynamic diameter≤2.5μm,PM_(2.5))increases the morbidity and mortality of respiratory diseases.Emerging evidence suggests that human circulating extracellular vesicles(EVs)may offer protective effects against injury caused by particulate matter.Currently,however,whether EVs attenuate PM_(2.5)-induced A549 cell apoptosis is unknown.Methods EVs were isolated from the serum of healthy subjects,quantified via nanoparticle tracking analysis,and qualified by the marker protein CD63.PM_(2.5)-exposed(50μg/mL)A549 cells were pretreated with 10μg/mL EVs for 24 h.Cell viability,cell apoptosis,and AKT activation were assessed via Cell Counting Kit-8,flow cytometry,and Western blot,respectively.A rescue experiment was also performed using MK2206,an AKT inhibitor.Results PM_(2.5)exposure caused a 100%in crease in cell apoptosis.EVs treatme nt reduced cell apoptosis by 10%,promoted cell survival,and inhibited the PM_(2.5)-induced upregulation of Bax/Bcl2 and cleaved caspase 3/caspase 3 in PM_(2.5)-exposed A549 cells.Moreover,EVs treatment reversed PM_(2.5)-induced reductions in p-AKT^(Thr308)and p-AKT^(Ser473).A KT inhibition attenuated the anti-apoptotic effect of EVs treatment on PM_(2.5)-exposed A549 cells.Conclusions EVs treatment promotes cell survival and attenuates PM_(2.5)-induced cell apoptosis via AKT phosphorylation.Human serum-derived EVs may be an efficacious novel therapeutic strategy in PM_(2.5)-induced lung injury.展开更多
Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases(CVD).Functional and mechanistic studies that employ animal exercise...Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases(CVD).Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants,have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health.First,this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health.We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health.The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations.The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling.Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects.Moreover,we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD.We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise.We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.展开更多
Circular RNAs take crucial roles in several pathophysiological processes.The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown.Here,we report that circ-ZNF609 is upregul...Circular RNAs take crucial roles in several pathophysiological processes.The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown.Here,we report that circ-ZNF609 is upregulated during myocardial ischemia/reperfusion(I/R)remodeling.Knockdown of circ-ZNF609 protects against acute I/R injury and attenuates left ventricle dysfunction after I/R remodeling in vivo.In vitro,circ-ZNF609 regulates cardiomyocyte survival and proliferation via modulating the crosstalk between Hippo-YAP and Akt signaling.Mechanically,N6-methyladenosine-modification is involved in the regulatory role of circ-ZNF609 on YAP.An in-depth study indicates that knockdown of circ-ZNF609 decreases the expression of YTHDF3 and further fine-tuned the accessibility of Yap mRNA to YTHDF1 and YTHDF2 to regulate YAP expression.circ-ZNF609 knockdown represents a promising therapeutic strategy to combat the pathological process of myocardial I/R injury.展开更多
基金This work was supported by grants from the National Key Research and Development Project(2020YFA0803800 to YB)National Natural Science Foundation of China(82020108002 and 81911540486 to JX,81772444 to LW,81772466 to RD)+2 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(18410722200 and 17010500100 to JX)“Dawn”Program of the Shanghai Education Commission(19SG34 to JX)。
文摘Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated.Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection.However,standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective,high-quality animal studies using exercise to prevent and treat cardiovascular diseases.In our review,we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training,emphasizing the appropriate measurements and analysis in these chronic exercise models.We also provide recommendations for optimal design of animal exercise studies in cardiovascular research,including the choice of exercise models,control of exercise protocols,exercise at different stages of disease,and other considerations,such as age,sex,and genetic background.We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.
基金supported by National Natural Science Foundation of China(No.82302401 to YW)the grant from Science and Technology Commission of Shanghai Municipality(Nos.23410750100,20DZ2255400 and 21XD1421300 to JX)the“Dawn”Program of Shanghai Education Commission(No.19SG34 to JX).
文摘Cardiovascular diseases cause significant morbidity and mortality worldwide.Engineered cardiac organoids are being developed and used to replicate cardiac tissues supporting cardiac morphogenesis and development.These organoids have applications in drug screening,cardiac disease models and regenerative medicine.Therefore,a thorough understanding of cardiac organoids and a comprehensive overview of their development are essential for cardiac tissue engineering.This review summarises different types of cardiac organoids used to explore cardiac function,including those based on co-culture,aggregation,scaffolds,and geometries.The self-assembly of monolayers,multilayers and aggravated cardiomyocytes forms biofunctional cell aggregates in cardiac organoids,elucidating the formation mechanism of scaffold-free cardiac organoids.In contrast,scaffolds such as decellularised extracellular matrices,three-dimensional hydrogels and bioprinting techniques provide a supportive framework for cardiac organoids,playing a crucial role in cardiac development.Different geometries are engineered to create cardiac organoids,facilitating the investigation of intrinsic communication between cardiac organoids and biomechanical pathways.Additionally,this review emphasises the relationship between cardiac organoids and the cardiac system,and evaluates their clinical applications.This review aims to provide valuable insights into the study of three-dimensional cardiac organoids and their clinical potential.
基金supported by grants from the National Natural Science Foundation of China(81722008,91639101,and81570362 to JX and 81800358 to LW)the Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)+1 种基金the Science and TechnologyCommission of Shanghai Municipality(17010500100 to JX)the development fund for Shanghai talents(to JX)
文摘Exercise training is beneficial to the cardiovascular system. MicroRNAs (miRNAs, miRs) are a class of conserved non-coding RNAs and play a wide-ranging role in the regulation of eukaryotic gene expression. Exercise training alters the expression levels of large amounts ofmiRNAs in the heart. In addition, circulating miRNAs appear to be regulated by exercise training. In this review, we will summarize recent advances in the regulation of miRNAs during physical exercise intervention in various cardiovascular diseases, including pathologic cardiac hypertrophy, myocardial fibrosis, ischemia-reperfusion injury, myocardial infarction, and heart failure. The regulatory role of circulating miRNAs after exercise training was also reviewed. In conclusion, miRNAs might be a valuable target for treatment of cardiovascular diseases and have great potential as biomarkers for assessment of physical performance.2018 Published by Elsevier B.V.on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/).
基金supported by the grants from National Key Research and Development Project(2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX,81970335 and 82170285 to YB)+4 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 18410722200 to JX)the“Dawn”Program of Shanghai Education Commission(19SG34 to JX)the Shanghai Rising-Star Program(19QA1403900 to YB)the Science and Technology Commission of Shanghai Municipality(21SQBS00100 to YB).
文摘Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.
文摘Cardiovascular disease(CVD)is a major cause of mortality and morbidity worldwide.In China,it is estimated that 330 million people are CVD patients.With the rapid aging of populations around the world,the number of CVD patients and death due to CVD are continuously rising.1 Exercise and physical activity have been recognized as economical and effective ways to enhance cardiovascular health and reduce CVD.Pathways mediating the cardiovascular benefits of exercise are promising therapeutic targets for CVD.
基金supported by grants from National Key Research and Development Project(2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX)+1 种基金a grant from Science and Technology Commission of Shanghai Municipality(21XD1421300 and 20DZ2255400 to JX)the“Dawn”Program of Shanghai Education Commission(19SG34 to JX and the American Heart Association(20AIREA35080151 to SCK).
文摘Cardiac substrate utilization remains a critical focus for the research community.1 Research has acknowledged the role of metabolic flexibility in the development and progression of cardiac dysfunction during a variety of diseases and conditions.2,3 Under resting basal conditions,the heart relies on fatty acid metabolism as the primary energy source with glucose,lactate,ketone bodies,pyruvate,acetate,and branched-chain amino acids contributing as substrates depending on substrate availability,hormonal status,and myocardial conditioning.4 In addition to pathological states,physiological states,such as acute exercise,induce dynamic changes in substrate metabolism,including nearly a 10-fold increase in myocardial oxygen consumption.3,5 To meet the increased demand for energy during and after a bout of exercise,the heart muscle must exhibit metabolic flexibility and selectively utilize different substrates for adenosine triphosphate production.Moreover,metabolic substrate adaptations depend on the frequency,intensity,duration,and mode of exercise while multiple metabolic fluxes,such as the use,storage and mobilization of substrates must be coordinated to maintain energy homeostasis.1,2 Although many different processes of exercise-induced regulation and metabolic remodeling have been identified,35 the effect of exercise on cellular metabolism and the landscape of metabolic pathway regulation in response to both acute exercise and chronic exercise training remain unclear.
基金Among these,patents were licensed to Bayer(WO2014020041-A1 and WO2014020043-A1)Bristol-Myers Squibb(WO2008057863-A1)+4 种基金Osasuna Therapeutics(WO2019057742A1)Pharmamar(WO2022049270A1 and WO2022048775-A1)Raptor Pharmaceuticals(EP2664326-A1)Samsara Therapeutics(GB202017553D0)Therafast Bio(EP3684471A1).The other authors declare that they have no competing interests.
文摘Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.
基金the National Natural Science Foundation of China(No.82020108002&82225005 to JJ Xiao,82270291 to LJ Wang)the Science and Technology Commission of Shanghai,China(No.23410750100,20DZ2255400&21XD1421300 to JJ Xiao)the Natural Science Foundation of Shanghai,China(No.23ZR1423000 to LJ Wang).
文摘RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RNAs(ncRNAs)are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions.Similar to mRNAs,m^(6)A deposition is observed in ncRNAs.Studying RNA m^(6)A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications.In this review,we summarized the recent research findings regarding the mutual regulation between RNA m^(6)A modification and ncRNAs(with a specific focus on microRNAs,long non-coding RNAs,and circular RNAs)and their functions.We also discussed the challenges of m^(6)A-containing ncRNAs and RNA m^(6)A as therapeutic targets in human diseases and their future perspective in translational roles.
基金supported by grants from the National Key Research and Development Project(2020YFA0803800 to JL,2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX)+2 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 18410722200 to JX)the“Dawn”Program of the Shanghai Education Commission(19SG34 to JX).
文摘Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.
基金supported by grants from the National Natural Science Foundation of China(81722008,91639101,and 81570362 to J.Xiao,and 81800358 to L.Wang)from the Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to J.Xiao)+1 种基金from the Science and Technology Commission of Shanghai Municipality(17010500100 and 18410722200 to J.Xiao)from the development fund for Shanghai talents(to J.Xiao)。
文摘Cardiovascular disease is the leading cause of human death worldwide. Autophagy is an evolutionarily conserved degradation pathway,which is a highly conserved cellular degradation process in which lysosomes decompose their own organelles and recycle the resulting macromolecules.Autophagy is critical in maintaining cardiovascular homeostasis and function, and excessive or insufficient autophagy or autophagic flux can lead to cardiovascular disease. Enormous evidence indicates that exercise training plays a beneficial role in the prevention and treatment of cardiovascular diseases. The regulation of autophagy during exercise is a bidirectional process. For cardiovascular disease caused by either insufficient or excessive autophagy, exercise training restores normal autophagy function and delays the progression of cardiovascular disease.An in-depth exploration and discussion of exercise-mediated regulation of autophagy in the cardiovascular system can broaden our view about the prevention of various autophagy-related diseases through exercise training. In this article, we review autophagy and its related signaling pathways,as well as autophagy-dependent beneficial effects of exercise in cardiovascular system.
基金the grants from National Key Research and Development Project(2018YFE0113500 to J.X.)National Natural Science Foundation of China(82020108002 and 82225005 to J.X.and 82270291 to L.W.)+3 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to J.X.)the grant from Science and Technology Commission of Shanghai Municipality(21XD1421300 and 20DZ2255400 to J.X.)the“Dawn”Program of Shanghai Education Commission(19SG34 to J.X.)ZonMw PSIDER grant(no.10250022110004)to J.P.G.S.
文摘Cardiovascular disease is one of the leading causes of mortality worldwide.Recent studies have shown that circular RNAs(circRNAs)have emerged as important players in the prevention and treatment of cardiovascular diseases.circRNAs are a class of endogenous noncoding RNAs that are generated by back-splicing and are involved in many pathophysiological processes.In this review,we outline the current research progress on the regulatory roles of circRNAs in cardiovascular diseases.Further,new technologies and methods available for identifying,validating,synthesizing,and analyzing circRNAs,as well as their applications in therapeutics,are highlighted here.Moreover,we summarize the increasing insights into the potential use of circRNAs as circulating diagnostic and prognostic biomarkers.Finally,we discuss the prospects and challenges of circRNA therapeutic applications for cardiovascular disease therapy,with a particular focus on developing circRNA synthesis and engineering delivery systems.
基金supported by grants from the National Natural Science Foundation of China[NSFC31500618,awarded to GAO JNSFC82000253,awarded to WANG HY]sponsored by Shanghai Sailing Program[20YF1414000 to WANG HY]。
文摘Objective Epidemiological studies reveal that exposure to fine particulate matter(aerodynamic diameter≤2.5μm,PM_(2.5))increases the morbidity and mortality of respiratory diseases.Emerging evidence suggests that human circulating extracellular vesicles(EVs)may offer protective effects against injury caused by particulate matter.Currently,however,whether EVs attenuate PM_(2.5)-induced A549 cell apoptosis is unknown.Methods EVs were isolated from the serum of healthy subjects,quantified via nanoparticle tracking analysis,and qualified by the marker protein CD63.PM_(2.5)-exposed(50μg/mL)A549 cells were pretreated with 10μg/mL EVs for 24 h.Cell viability,cell apoptosis,and AKT activation were assessed via Cell Counting Kit-8,flow cytometry,and Western blot,respectively.A rescue experiment was also performed using MK2206,an AKT inhibitor.Results PM_(2.5)exposure caused a 100%in crease in cell apoptosis.EVs treatme nt reduced cell apoptosis by 10%,promoted cell survival,and inhibited the PM_(2.5)-induced upregulation of Bax/Bcl2 and cleaved caspase 3/caspase 3 in PM_(2.5)-exposed A549 cells.Moreover,EVs treatment reversed PM_(2.5)-induced reductions in p-AKT^(Thr308)and p-AKT^(Ser473).A KT inhibition attenuated the anti-apoptotic effect of EVs treatment on PM_(2.5)-exposed A549 cells.Conclusions EVs treatment promotes cell survival and attenuates PM_(2.5)-induced cell apoptosis via AKT phosphorylation.Human serum-derived EVs may be an efficacious novel therapeutic strategy in PM_(2.5)-induced lung injury.
基金supported by the grants from National Key Research and Development Project(2018YFE0113500 to J.X.)ational Natural Science Foundation of China(82020108002 and 81911540486 to J.X.,81970335 and 82170285 to Y.H.B.)+3 种基金the grant from Science and Technology Commission of Shanghai Municipality(21XD1421300 and 20DZ2255400 to J.X.)the“Dawn”Program of Shanghai Education Commission(19SG34 to J.X.)Shanghai Rising-Star Program(19QA1403900 to Y.H.B.)the grant from Science and Technology Commission of Shanghai Municipality(21SQBS00100 to Y.H.B.).
文摘Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases(CVD).Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants,have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health.First,this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health.We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health.The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations.The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling.Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects.Moreover,we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD.We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise.We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.
基金the National Key Research and Development Project(2018YFE0113500 to J.J.X.)National Natural Science Foundation of China(82020108002 and 81911540486 to J.J.X.,81800358 to L.J.W.,and 82070411 to J.H.X.)+3 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to J.J.X.)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 21XD1421300 to J.J.X.)“Dawn”Program of Shanghai Municipal Education Com mission(19SG34 to J.J.X.)Natural Science Foundation of Shanghai(19ZR1474100 to L.J.W.and 19ZR1450400 to H.B.W.).
文摘Circular RNAs take crucial roles in several pathophysiological processes.The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown.Here,we report that circ-ZNF609 is upregulated during myocardial ischemia/reperfusion(I/R)remodeling.Knockdown of circ-ZNF609 protects against acute I/R injury and attenuates left ventricle dysfunction after I/R remodeling in vivo.In vitro,circ-ZNF609 regulates cardiomyocyte survival and proliferation via modulating the crosstalk between Hippo-YAP and Akt signaling.Mechanically,N6-methyladenosine-modification is involved in the regulatory role of circ-ZNF609 on YAP.An in-depth study indicates that knockdown of circ-ZNF609 decreases the expression of YTHDF3 and further fine-tuned the accessibility of Yap mRNA to YTHDF1 and YTHDF2 to regulate YAP expression.circ-ZNF609 knockdown represents a promising therapeutic strategy to combat the pathological process of myocardial I/R injury.