Fine particulate matter(PM_(2.5))is a significant risk factor for birth defects.As the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted grow...Fine particulate matter(PM_(2.5))is a significant risk factor for birth defects.As the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted growing concern.Despite several studies supporting the cardiac developmental toxicity of PM_(2.5),the diverse study types,models,and end points have prevented the integration of mechanisms.In this Review,we present an adverse outcome pathway framework to elucidate the association between PM_(2.5)-induced molecular initiating events and adverse cardiac developmental outcomes.Activation of the aryl hydrocarbon receptor(AhR)and excessive generation of reactive oxygen species(ROS)were considered as molecular initiating events.The excessive production of ROS induced oxidative stress,endoplasmic reticulum stress,DNA damage,and inflammation,resulting in apoptosis.The activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte differentiation.Impaired cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and function.All of the aforementioned events have been identified as key events(KEs).The culmination of these KEs ultimately led to the adverse outcome,an increased morbidity of congenital heart defects(CHDs).This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM_(2.5).展开更多
The Hippo signaling pathway was originally discovered in Drosophila and shown to be critical for organ size control and tumorigenesis. This pathway consists of a cascade of kinases and several adaptors that lead to th...The Hippo signaling pathway was originally discovered in Drosophila and shown to be critical for organ size control and tumorigenesis. This pathway consists of a cascade of kinases and several adaptors that lead to the phosphorylation and inhibition, through nuclear exclusion, of the transcriptional cofactor Yorkie in Drosophila or YAP （yes associated protein） in mammals. Recent studies demonstrate that cardiac-specific deletion of the Hippo pathway kinase Mst （STE20-1ike protein kinases） co-activator WW45 （WW domain-containing adaptor 45）, Mstl, Mst2, or Lats2 （large tumor suppressor homologue 2） in mice result in over-grown hearts with elevated cardiomyocyte proliferation. Consistent with these observations, over-expression of YAP in the mouse embryonic heart increases heart size and promotes cardiac regeneration and contractility after myocardial infarction by inducing cardiomyocyte proliferation, whereas deletion of YAP in the mouse heart impedes cardiomyocyte proliferation, causing myocardial hypoplasia and embryonic or premature lethality. YAP has also been shown to play an important role in the vascular system. Specific-deletion of YAP from vascular smooth muscle cells in mice results in aberrant development of large arteries with a hypoplastic arterial wall phenotype. Hippo-YAP signaling cross-talks with other signaling pathways such as IGF （insulin-like growth factor） and Wnt signaling to promote heart growth by increasing expression of cell cycle genes. The purpose of this review is to summarize these recent findings and discuss potential diagnostic or therapeutic strategies in cardiovascular system based on manipulating the Hippo-YAP signaling.展开更多
Cardiac resident macrophages (CRMs) are the main population of cardiac immune cells. The role of these cells in regeneration, functional remodeling, and repair after cardiac injury is always the focus of research. How...Cardiac resident macrophages (CRMs) are the main population of cardiac immune cells. The role of these cells in regeneration, functional remodeling, and repair after cardiac injury is always the focus of research. However, in recent years, their dynamic changes and contributions in physiological states have a significant attention. CRMs have specific phenotypes and functions in different cardiac chambers or locations of the heart and at different stages. They further show specific differentiation and development processes. The present review will summarize the new progress about the spatiotemporal distribution, potential developmental regulation, and their roles in cardiac development and aging as well as the translational potential of CRMs on cardiac diseases. Of course, the research tools for CRMs, their respective advantages and disadvantages, and key issues on CRMs will further be discussed.展开更多
Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for...Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for heart failure.Here we present a review on zebrafish heart development and regeneration,with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart,as well as cellular and molecular programs in adult zebrafish heart regeneration.We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration.A brief perspective highlights several important and promising research areas in this exciting field.展开更多
Quantum dots(QDs)are new types of nanomaterials.Few studies have focused on the effect of different surface modified QDs on embryonic development.Herein,we compared the in vivo toxicity of Cd Se/Zn S QDs with carboxyl...Quantum dots(QDs)are new types of nanomaterials.Few studies have focused on the effect of different surface modified QDs on embryonic development.Herein,we compared the in vivo toxicity of Cd Se/Zn S QDs with carboxyl(-COOH)and amino(-NH 2)modification using zebrafish embryos.After exposure,the two Cd Se/Zn S QDs decreased the survival rate,hatching rate,and embryo movement of zebrafish.Moreover,we found QDs attached to the embryo membrane before hatching and the eyes,yolk and heart after hatching.The attached amount of carboxyl QDs was more.Consistently,the Cd content in embryos and larvae was higher in carboxyl QD-treatment.We further observed that the two QDs caused zebrafish pericardial edema and cardiac dysfunction.In line with it,both carboxyl and amino QDs upregulated the transcription levels of cardiac development-related genes,and the levels were higher in carboxyl QD-treated groups.Furthermore,the chelator of Cd^2+diethylene triamine pentacetate acid could partially rescued the developmental toxicity caused by the two types of QDs suggesting that both the nature of QDs and the release of Cd^2+contribute to the developmental toxicity.In conclusion,the two Cd Se/ZnS QDs have developmental toxicity and affect the cardiac development,and the carboxyl QDs is more toxic possibly due to the higher affinity and more release to embryos and larvae.Our study provides new knowledge that the surface functional modification of QDs is critical on the development on aquatic species,which is beneficial to develop and applicate QDs more safely and environmentfriendly.展开更多
Cardiac ankyrin repeat protein （CARP） not only serves as an important component of muscle sarcomere in the cytoplasm, but also acts as a transcription co-factor in the nucleus. Previous studies have demonstrated tha...Cardiac ankyrin repeat protein （CARP） not only serves as an important component of muscle sarcomere in the cytoplasm, but also acts as a transcription co-factor in the nucleus. Previous studies have demonstrated that CARP is up-regulated in some cardiovascular disorders and muscle diseases; however, its role in these diseases remains controversial now. In this review, we will discuss the continued progress in the research related to CARP, including its discovery, structure, and the role it plays in cardiac development and heart diseases.展开更多
Chamber maturation is a significant process in cardiac development. Disorders of this crucial process lead to a range of congenital heart defects. Foxc1a is a critical transcription factor reported to regulate the spe...Chamber maturation is a significant process in cardiac development. Disorders of this crucial process lead to a range of congenital heart defects. Foxc1a is a critical transcription factor reported to regulate the specification of cardiac progenitor cells. However, little is known about the role of Foxc1a in modulating chamber maturation. Previously, we reported that foxc1a-null zebrafish embryos exhibit disrupted heart structures and functions. In this study, we observe that ventricle structure and cardiomyocyte proliferation are abolished during chamber maturation in foxc1a-null zebrafish embryos. To observe the endogenous localization of Foxc1a in the hearts of living embryos, we insert eyfp at the foxc1a genomic locus using TALEN. Analysis of the knockin zebrafish show that foxc1a is widely expressed in ventricular cardiomyocytes during chamber development. Cardiac RNA sequencing analysis reveals the downregulated expression of the Hippo signaling effector wwtr1. Dual-luciferase and chromatin immunoprecipitation assays reveal that Foxc1a can bind directly to three sites in the wwtr1 promoter region. Furthermore, wwtr1m RNA overexpression is sufficient to reverse the ventricle defects during chamber maturation. Conditional overexpression of nkx2.5 also partially rescues the ventricular defects during chamber development. These findings demonstrate that wwtr1 and nkx2.5 are direct targets of Foxc1a during ventricular chamber maturation.展开更多
基金supported by the National Key R&D Program of China(2022YFA0806900).
文摘Fine particulate matter(PM_(2.5))is a significant risk factor for birth defects.As the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted growing concern.Despite several studies supporting the cardiac developmental toxicity of PM_(2.5),the diverse study types,models,and end points have prevented the integration of mechanisms.In this Review,we present an adverse outcome pathway framework to elucidate the association between PM_(2.5)-induced molecular initiating events and adverse cardiac developmental outcomes.Activation of the aryl hydrocarbon receptor(AhR)and excessive generation of reactive oxygen species(ROS)were considered as molecular initiating events.The excessive production of ROS induced oxidative stress,endoplasmic reticulum stress,DNA damage,and inflammation,resulting in apoptosis.The activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte differentiation.Impaired cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and function.All of the aforementioned events have been identified as key events(KEs).The culmination of these KEs ultimately led to the adverse outcome,an increased morbidity of congenital heart defects(CHDs).This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM_(2.5).
基金supported by a grant(No.R01HL109605)from theNational Heart,Lung,and Blood Institute,NIH
文摘The Hippo signaling pathway was originally discovered in Drosophila and shown to be critical for organ size control and tumorigenesis. This pathway consists of a cascade of kinases and several adaptors that lead to the phosphorylation and inhibition, through nuclear exclusion, of the transcriptional cofactor Yorkie in Drosophila or YAP （yes associated protein） in mammals. Recent studies demonstrate that cardiac-specific deletion of the Hippo pathway kinase Mst （STE20-1ike protein kinases） co-activator WW45 （WW domain-containing adaptor 45）, Mstl, Mst2, or Lats2 （large tumor suppressor homologue 2） in mice result in over-grown hearts with elevated cardiomyocyte proliferation. Consistent with these observations, over-expression of YAP in the mouse embryonic heart increases heart size and promotes cardiac regeneration and contractility after myocardial infarction by inducing cardiomyocyte proliferation, whereas deletion of YAP in the mouse heart impedes cardiomyocyte proliferation, causing myocardial hypoplasia and embryonic or premature lethality. YAP has also been shown to play an important role in the vascular system. Specific-deletion of YAP from vascular smooth muscle cells in mice results in aberrant development of large arteries with a hypoplastic arterial wall phenotype. Hippo-YAP signaling cross-talks with other signaling pathways such as IGF （insulin-like growth factor） and Wnt signaling to promote heart growth by increasing expression of cell cycle genes. The purpose of this review is to summarize these recent findings and discuss potential diagnostic or therapeutic strategies in cardiovascular system based on manipulating the Hippo-YAP signaling.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.32370984 and 82101914)Six Talent Peaks Project in Jiangsu Province(2019-WSN-122,China)+2 种基金Projects of International Cooperation from Jiangsu Province(BX2019100,China)Key Funds from the Health Commission of Jiangsu Province(ZD2021009,China)the Social Development Foundation of Zhenjiang(SH2022060,China).
文摘Cardiac resident macrophages (CRMs) are the main population of cardiac immune cells. The role of these cells in regeneration, functional remodeling, and repair after cardiac injury is always the focus of research. However, in recent years, their dynamic changes and contributions in physiological states have a significant attention. CRMs have specific phenotypes and functions in different cardiac chambers or locations of the heart and at different stages. They further show specific differentiation and development processes. The present review will summarize the new progress about the spatiotemporal distribution, potential developmental regulation, and their roles in cardiac development and aging as well as the translational potential of CRMs on cardiac diseases. Of course, the research tools for CRMs, their respective advantages and disadvantages, and key issues on CRMs will further be discussed.
基金supported by the grants from the National Basic Research Program of China(Nos.2010CB529503 and 2012CB944501)the National Science Foundation of China(Nos.30971662 and 31000644)
文摘Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine,one of the most urgent clinical needs for heart failure.Here we present a review on zebrafish heart development and regeneration,with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart,as well as cellular and molecular programs in adult zebrafish heart regeneration.We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration.A brief perspective highlights several important and promising research areas in this exciting field.
基金the National Natural Science Foundation of China(No.31971234)the Fundamental Research Funds for the Central Universities(No.20720180045)the Open Research Fund of State Key Laboratory of Cellular Stress Biology,Xiamen University(No.SKLCSB2019KF001)。
文摘Quantum dots(QDs)are new types of nanomaterials.Few studies have focused on the effect of different surface modified QDs on embryonic development.Herein,we compared the in vivo toxicity of Cd Se/Zn S QDs with carboxyl(-COOH)and amino(-NH 2)modification using zebrafish embryos.After exposure,the two Cd Se/Zn S QDs decreased the survival rate,hatching rate,and embryo movement of zebrafish.Moreover,we found QDs attached to the embryo membrane before hatching and the eyes,yolk and heart after hatching.The attached amount of carboxyl QDs was more.Consistently,the Cd content in embryos and larvae was higher in carboxyl QD-treatment.We further observed that the two QDs caused zebrafish pericardial edema and cardiac dysfunction.In line with it,both carboxyl and amino QDs upregulated the transcription levels of cardiac development-related genes,and the levels were higher in carboxyl QD-treated groups.Furthermore,the chelator of Cd^2+diethylene triamine pentacetate acid could partially rescued the developmental toxicity caused by the two types of QDs suggesting that both the nature of QDs and the release of Cd^2+contribute to the developmental toxicity.In conclusion,the two Cd Se/ZnS QDs have developmental toxicity and affect the cardiac development,and the carboxyl QDs is more toxic possibly due to the higher affinity and more release to embryos and larvae.Our study provides new knowledge that the surface functional modification of QDs is critical on the development on aquatic species,which is beneficial to develop and applicate QDs more safely and environmentfriendly.
基金Project supported by the National Natural Science Foundation of China(No.31171392)
文摘Cardiac ankyrin repeat protein （CARP） not only serves as an important component of muscle sarcomere in the cytoplasm, but also acts as a transcription co-factor in the nucleus. Previous studies have demonstrated that CARP is up-regulated in some cardiovascular disorders and muscle diseases; however, its role in these diseases remains controversial now. In this review, we will discuss the continued progress in the research related to CARP, including its discovery, structure, and the role it plays in cardiac development and heart diseases.
基金supported by the National Natural Science Foundation of China (31970769 and 31671518)。
文摘Chamber maturation is a significant process in cardiac development. Disorders of this crucial process lead to a range of congenital heart defects. Foxc1a is a critical transcription factor reported to regulate the specification of cardiac progenitor cells. However, little is known about the role of Foxc1a in modulating chamber maturation. Previously, we reported that foxc1a-null zebrafish embryos exhibit disrupted heart structures and functions. In this study, we observe that ventricle structure and cardiomyocyte proliferation are abolished during chamber maturation in foxc1a-null zebrafish embryos. To observe the endogenous localization of Foxc1a in the hearts of living embryos, we insert eyfp at the foxc1a genomic locus using TALEN. Analysis of the knockin zebrafish show that foxc1a is widely expressed in ventricular cardiomyocytes during chamber development. Cardiac RNA sequencing analysis reveals the downregulated expression of the Hippo signaling effector wwtr1. Dual-luciferase and chromatin immunoprecipitation assays reveal that Foxc1a can bind directly to three sites in the wwtr1 promoter region. Furthermore, wwtr1m RNA overexpression is sufficient to reverse the ventricle defects during chamber maturation. Conditional overexpression of nkx2.5 also partially rescues the ventricular defects during chamber development. These findings demonstrate that wwtr1 and nkx2.5 are direct targets of Foxc1a during ventricular chamber maturation.
