RESUMO
Peroxisome proliferator activated receptors, including PPARα, PPARß/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose and lipid metabolism and are also supposed to reduce inflammation and atherosclerosis. All PPARs are involved in angiogenesis, a process critically involved in cardiovascular pathology. Synthetic specific agonists exist for all PPARs. PPARα agonists (fibrates) are used to treat dyslipidemia by decreasing triglyceride and increasing high-density lipoprotein (HDL) levels. PPARγ agonists (thiazolidinediones) are used to treat Type 2 diabetes mellitus by improving insulin sensitivity. PPARα/γ (dual) agonists are supposed to treat both pathological conditions at once. In contrast, PPARß/δ agonists are not in clinical use. Although activators of PPARs were initially considered to have favorable effects on the risk factors for cardiovascular disease, their cardiovascular safety is controversial. Here, we discuss the implications of PPARs in vascular biology regarding cardiac pathology and focus on the outcomes of clinical studies evaluating their benefits in cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , PPAR beta , Humanos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , PPAR gama/metabolismo , PPAR alfa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , PPAR beta/uso terapêuticoRESUMO
During development, the heart is the first organ to form and function [...].
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Cardiopatias , Coração , Coração/crescimento & desenvolvimentoRESUMO
The heart, which is the first organ to develop in the embryo, is indispensable for vital functions throughout life [...].
Assuntos
Regulação da Expressão Gênica , Coração , Embrião de Mamíferos , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
Nearly three decades ago, the Wilms' tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1.
Assuntos
Coração/crescimento & desenvolvimento , Miocárdio/metabolismo , Proteínas WT1/metabolismo , Animais , Transição Epitelial-Mesenquimal/fisiologia , Expressão Gênica/genética , Coração/embriologia , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Pericárdio/embriologia , Pericárdio/patologia , Fatores de Transcrição/metabolismo , Proteínas WT1/genética , Proteínas WT1/fisiologiaRESUMO
The Wilms' tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, and fibroblasts. Expression of Wt1 in cardiomyocytes has been suggested but remained a controversial issue, as well as the role of Wt1 in cardiomyocyte development and regeneration after injury. We determined cardiac Wt1 expression during embryonic development, in the adult, and after cardiac injury by quantitative RT-PCR and immunohistochemistry. As in vitro model, phenotypic cardiomyocyte differentiation, i.e., the appearance of rhythmically beating clones from mouse embryonic stem cells (mESCs) and associated changes in gene expression were analyzed. We detected Wt1 in cardiomyocytes from embryonic day (E10.5), the first time point investigated, until adult age. Cardiac Wt1 mRNA levels decreased during embryonic development. In the adult, Wt1 was reactivated in cardiomyocytes 48 h and 3 weeks following myocardial infarction. Wt1 mRNA levels were increased in differentiating mESCs. Overexpression of Wt1(-KTS) and Wt1(+KTS) isoforms in ES cells reduced the fraction of phenotypically cardiomyocyte differentiated clones, which was preceded by a temporary increase in c-kit expression in Wt1(-KTS) transfected ES cell clones and induction of some cardiomyocyte markers. Taken together, Wt1 shows a dynamic expression pattern during cardiomyocyte differentiation and overexpression in ES cells reduces their phenotypical cardiomyocyte differentiation.
Assuntos
Diferenciação Celular , Células-Tronco Embrionárias Murinas/citologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/citologia , Proteínas WT1/metabolismo , Animais , Feminino , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas WT1/genéticaRESUMO
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. They exhibit tissue and cell type-specific expression patterns and functions. Besides the established notion of the therapeutic potential of PPAR agonists for the treatment of glucose and lipid disorders, more recent data propose specific PPAR ligands as potential therapies for cardiovascular diseases. In this review, we focus on the knowledge of PPAR function in myocardial infarction, a severe pathological condition for which therapeutic use of PPAR modulation has been suggested.
Assuntos
Doenças Cardiovasculares/metabolismo , Infarto do Miocárdio/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Doenças Cardiovasculares/genética , Humanos , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genéticaRESUMO
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.
Assuntos
Artrite Reumatoide/metabolismo , Doenças Cardiovasculares/metabolismo , Endometriose/metabolismo , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Doenças Placentárias/metabolismo , Doenças Retinianas/metabolismo , Animais , Células Endoteliais/metabolismo , Feminino , Humanos , Ligantes , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Gravidez , Transdução de SinaisRESUMO
Coronary artery anomalies are common congenital disorders with serious consequences in adult life. Coronary circulation begins when the coronary stems form connections between the aorta and the developing vascular plexus. We recently identified the WNT signaling modulator R-spondin 3 (Rspo3), as a crucial regulator of coronary stem proliferation. Using expression analysis and tissue-specific deletion we now demonstrate that Rspo3 is primarily produced by cardiomyocytes. Moreover, we have employed CRISPR/Cas9 technology to generate novel Lgr4-null alleles that showed a significant decrease in coronary stem proliferation and thus phenocopied the coronary artery defects seen in Rspo3 mutants. Interestingly, Lgr4 mutants displayed slightly hypomorphic right ventricles, an observation also made after myocardial specific deletion of Rspo3. These results shed new light on the role of Rspo3 in heart development and demonstrate that LGR4 is the principal R-spondin 3 receptor in the heart.
Assuntos
Vasos Coronários/embriologia , Coração/embriologia , Miócitos Cardíacos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Trombospondinas/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Circulação Coronária/fisiologia , Vasos Coronários/citologia , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Receptores Acoplados a Proteínas G/genética , Trombospondinas/genéticaRESUMO
Cdk9 is the catalytic core of the positive transcription elongation factor b (P-TEFb) and regulates transcriptional elongation factors by phosphorylation of RNA pol II. Apart from its role on myogenic gene expression, Cdk9 regulation of muscle-specific microRNAs in the early stage of cardiomyogenesis is poorly understood. Here we demonstrate that Cdk9 not only regulates myogenic transcription factors, but also controls muscle-specific microRNAs. During cardiac differentiation of mouse embryonic stem cells, high Cdk9 expression preceded up-regulation of miR-1. To investigate potential regulatory roles of Cdk9 on cardiac microRNAs and myogenesis genes, we overexpressed Cdk9 in myoblast C2C12 cells, which resulted in significant induction of miR-1 and miR-206, while miR-133 was downregulated. Moreover, expression levels of MyoD and Srf, key regulators of myogenesis, also increased in cells with overexpression of Cdk9. We further observed Cdk9-mediated apoptosis in C2C12 cells corresponding to induction of miR-1 expression levels. Thus, Cdk9 plays a complex role in myocyte progenitor differentiation and apoptosis by regulating myogenic protein and muscle-specific microRNA expression. J. Cell. Biochem. 119: 547-554, 2018. © 2017 Wiley Periodicals, Inc.
Assuntos
Apoptose , Quinase 9 Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Desenvolvimento Muscular , Mioblastos Cardíacos/metabolismo , Animais , Linhagem Celular , Quinase 9 Dependente de Ciclina/genética , Camundongos , MicroRNAs/genética , Mioblastos Cardíacos/citologiaRESUMO
Andersen's syndrome (AS) is a rare autosomal disorder that has been defined by the triad of periodic paralysis, cardiac arrhythmia, and developmental anomalies. AS has been directly linked to over 40 different autosomal dominant negative loss-of-function mutations in the KCNJ2 gene, encoding for the tetrameric strong inward rectifying K+ channel KIR2.1. While KIR2.1 channels have been suggested to contribute to setting the resting membrane potential (RMP) and to control the duration of the action potential (AP) in skeletal and cardiac muscle, the mechanism by which AS mutations produce such complex pathophysiological symptoms is poorly understood. Thus, we use an adenoviral transduction strategy to study in vivo subcellular distribution of wild-type (WT) and AS-associated mutant KIR2.1 channels in mouse skeletal muscle. We determined that WT and D71V AS mutant KIR2.1 channels are localized to the sarcolemma and the transverse tubules (T-tubules) of skeletal muscle fibers, while the ∆314-315 AS KIR2.1 mutation prevents proper trafficking of the homo- or hetero-meric channel complexes. Whole-cell voltage-clamp recordings in individual skeletal muscle fibers confirmed the reduction of inwardly rectifying K+ current (IK1) after transduction with ∆314-315 KIR2.1 as compared to WT channels. Analysis of skeletal muscle function revealed reduced force generation during isometric contraction as well as reduced resistance to muscle fatigue in extensor digitorum longus muscles transduced with AS mutant KIR2.1. Together, these results suggest that KIR2.1 channels may be involved in the excitation-contraction coupling process required for proper skeletal muscle function. Our findings provide clues to mechanisms associated with periodic paralysis in AS.
Assuntos
Síndrome de Andersen/genética , Técnicas de Silenciamento de Genes , Músculo Esquelético/patologia , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adenoviridae/metabolismo , Síndrome de Andersen/patologia , Síndrome de Andersen/fisiopatologia , Animais , Células COS , Chlorocebus aethiops , Proteínas de Fluorescência Verde/metabolismo , Humanos , Ativação do Canal Iônico , Contração Isométrica , Camundongos , Fadiga Muscular , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/fisiopatologiaRESUMO
In the published publication [...].
RESUMO
Nephrin (NPHS1) has been described as an important structural protein of kidney podocytes. Mutations in this gene lead to the Finnish-type congenital nephrotic syndrome. More recently, a role of nephrin as a signalling molecule in kidney podocytes has been identified. Here, we show that nephrin not only has a function in kidney podocytes, but is also required for cardiovascular development. Nephrin is expressed in the epicardium and coronary vessels during human and mouse embryonic development. Nephrin knockout embryos showed abnormal epicardial cell morphology and, at later stages of development, a reduced number of coronary vessels due to increased apoptosis, and in addition, cardiac fibrosis. Connexin 43, which is required for coronary vessel formation, was downregulated in nephrin knockout embryos. Expression of the p75NTR neurotrophin receptor, a known mediator of apoptosis, was increased in mutants. Furthermore, co-immunoprecipitation studies demonstrated a direct interaction of nephrin with p75NTR. Primary nephrin-deficient cardiac cells showed a 5-fold higher rate of apoptosis in response to progenitor of nerve growth factor compared with wild-type cells, which could be rescued by RNAi against p75NTR. Taken together, our data demonstrate that nephrin directly interacts with p75NTR and reveal an important role for nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells.
Assuntos
Vasos Coronários/embriologia , Proteínas de Membrana/metabolismo , Pericárdio/embriologia , Podócitos/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Apoptose , Conexina 43/genética , Conexina 43/metabolismo , Vasos Coronários/metabolismo , Regulação para Baixo , Eletroforese em Gel de Poliacrilamida , Humanos , Imunoprecipitação , Rim/citologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mutação , Organogênese/genética , Pericárdio/metabolismo , Receptores de Fator de Crescimento Neural/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Técnicas do Sistema de Duplo-HíbridoRESUMO
Aging is the leading predictive factor of many chronic diseases that account for most of the morbidity and mortality worldwide, i [...].
Assuntos
Envelhecimento , Senescência Celular , Humanos , Doença CrônicaRESUMO
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play important roles in cell proliferation, differentiation, metabolism, and cancer [...].
Assuntos
Neoplasias , Receptores Ativados por Proliferador de Peroxissomo , Humanos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares , Diferenciação Celular , Neoplasias/genética , Proliferação de CélulasRESUMO
The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.
RESUMO
Aberrations of specialized metabolic pathways might be implicated in the development of neoplasias. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with important functions in metabolism. PPARß/δ and PPARγ act in the proliferation and differentiation of adipose tissue progenitor cells. Thus, a potential use of PPARγ agonists for the treatment of liposarcoma had been suggested, but clinical trials failed to detect beneficial effects. We show here that PPARδ is highly expressed in liposarcoma compared to lipoma and correlates with proliferation. Stimulation of liposarcoma cell lines with a specific PPARδ agonist increases proliferation, which is abolished by a PPARδ-siRNA or a specific PPARδ antagonist. Expression of the adipose tissue secretory factor leptin is lower in liposarcoma compared to lipoma and leptin reduces proliferation of liposarcoma cell lines. PPARδ activation stimulates cell migration whereas leptin diminishes it. We demonstrate that PPARδ directly represses leptin as: (a) leptin becomes down-regulated upon PPARδ activation; (b) PPARδ represses leptin promoter activity in different sarcoma cell lines; (c) deletion of a PPAR/RxR binding element in the leptin promoter abolishes repression by PPARδ; and (d) in chromatin immunoprecipitation we confirm in vivo binding of PPARδ to the leptin promoter. Our data suggest inhibition of PPARδ as a potential novel strategy to reduce liposarcoma cell proliferation.
Assuntos
Lipossarcoma/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Feminino , Humanos , Leptina/antagonistas & inibidores , Leptina/biossíntese , Leptina/farmacologia , Lipoma/metabolismo , Lipoma/patologia , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , PPAR delta/farmacologia , PPAR delta/fisiologia , PPAR beta/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células Tumorais CultivadasRESUMO
Cells is experiencing a rapid increase in attractiveness and impact [...].
RESUMO
This introduction provides a preface to the section on "Cells of the Cardiovascular System" in the book entitled "Editor's Choice Articles in 2020-2021" [...].
Assuntos
Sistema CardiovascularRESUMO
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
Assuntos
Neoplasias , PPAR delta , PPAR beta , Ácidos Graxos/metabolismo , Humanos , Ligantes , PPAR alfa , Receptores Ativados por Proliferador de Peroxissomo/metabolismoRESUMO
It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.