RESUMO
PIWI-interacting RNAs (piRNAs) are recently discovered small non-coding RNAs consisting of 24-35 nucleotides, usually including a characteristic 5-terminal uridine and an adenosine at position 10. PIWI proteins can specifically bind to the unique structure of the 3' end of piRNAs. In the past, it was thought that piRNAs existed only in the reproductive system, but recently, it was reported that piRNAs are also expressed in several other human tissues with tissue specificity. Growing evidence shows that piRNAs and PIWI proteins are abnormally expressed in various diseases, including cancers, neurodegenerative diseases and ageing, and may be potential biomarkers and therapeutic targets. This review aims to discuss the current research status regarding piRNA biogenetic processes, functions, mechanisms and emerging roles in various diseases.
Assuntos
Envelhecimento , Neoplasias/patologia , Doenças Neurodegenerativas/patologia , RNA Interferente Pequeno/genética , Animais , Epigênese Genética , Humanos , Neoplasias/genética , Doenças Neurodegenerativas/genéticaRESUMO
Reduction oxidation (REDOX) reaction is crucial in life activities, and its dynamic balance is regulated by ROS. Reactive oxygen species (ROS) is associated with a variety of metabolic diseases involving in multiple cellular signalling in pathologic and physiological signal transduction. ROS are the by-products of numerous enzymatic reactions in various cell compartments, including the cytoplasm, cell membrane, endoplasmic reticulum (ER), mitochondria, and peroxisome. ROS signalling is not only involved in normal physiological processes but also causes metabolic dysfunction and maladaptive responses to inflammatory signals, which depends on the cell type or tissue environment. Excess oxidants are able to alter the normal structure and function of DNA, lipids, and proteins, leading to mutations or oxidative damage. Therefore, excessive oxidative stress is usually regarded as the cause of various pathological conditions, such as cancer, neurodegeneration, cardiovascular diseases (CVDs), diabetes, and kidney diseases. Currently, it has been possible to detect diabetes and other cardiac diseases by detecting derivatives accompanied by oxidative stress in vivo as biomarkers, but there is no effective method to treat these diseases. In consequence, it is essential for us to seek new therapy targeting these diseases through understanding the role of ROS signalling in regulating metabolic activity, inflammatory activation, and cardiac diseases related to metabolic dysfunction. In this review, we summarize the current literature on REDOX and its role in the regulation of cardiac metabolism and inflammation, focusing on ROS, local REDOX signalling pathways, and other mechanisms.
Assuntos
Doenças Cardiovasculares/metabolismo , Mitocôndrias/efeitos dos fármacos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N6-methyladenosine (m6A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR-PIWIL4 complexes directly interact with METTL3 and block the m6A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3ß and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR-METTL3-PARP10-NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.
Assuntos
Adenosina/análogos & derivados , Ventrículos do Coração/enzimologia , Hipertrofia Ventricular Esquerda/enzimologia , Metiltransferases/metabolismo , Miócitos Cardíacos/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Função Ventricular Esquerda , Adenosina/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metilação , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Proteínas Proto-Oncogênicas/genética , Estabilidade de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Remodelação VentricularRESUMO
BACKGROUND: The adult mammalian cardiomyocytes lose their proliferative capacity, which is responsible for cardiac dysfunction and heart failure following injury. The molecular mechanisms underlying the attenuation of adult cardiomyocyte proliferation remain largely unknown. Because long noncoding RNAs (lncRNAs) have a critical role in the development of cardiovascular problems, we investigated whether lncRNAs have any role in the regulation of cardiomyocyte proliferation and cardiac repair. METHODS: Using bioinformatics and initial analysis, we identified an lncRNA, named CPR (cardiomyocyte proliferation regulator), that has a potential regulatory role in cardiomyocyte proliferation. For in vivo experiments, we generated CPR knockout and cardiac-specific CPR-overexpressing mice. In isolated cardiomyocytes, we used adenovirus for silencing (CPR-small interfering RNA) or overexpressing CPR. To investigate the mechanisms of CPR function in cardiomyocyte proliferation, we performed various analyses including quantitative reverse transcription-polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), transcriptome analyses (microarray assay), RNA pull-down assay, and chromatin immunoprecipitation assay. RESULTS: CPR level is comparatively higher in the adult heart than in the fetal stage. The silencing of CPR significantly increased cardiomyocyte proliferation in postnatal and adult hearts. Moreover, CPR deletion restored the heart function after myocardial injury, which was evident from increased cardiomyocyte proliferation, improvement of myocardial function, and reduced scar formation. In contrast, the neonatal cardiomyocyte proliferation and cardiac regeneration were remarkably suppressed in CPR-overexpressing mice or adeno-associated virus serotype 9-CPR-overexpressing heart. These results indicate that CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration. Next, we found that CPR targets minichromosome maintenance 3, an initiator of DNA replication and cell cycle progression, to suppress cardiomyocyte proliferation. CPR silenced minichromosome maintenance 3 expression through directly interacting and recruiting DNMT3A to its promoter cysteine-phosphate-guanine sites, as evident from decreased minichromosome maintenance 3 promoter methylation and increased minichromosome maintenance 3 expression in CPR knocked-down cardiomyocytes and CPR knockout mouse heart. These results were confirmed in CPR-overexpressing cardiomyocytes and CPR-overexpressing mouse heart. CONCLUSIONS: Together, our findings identified that CPR is a suppressor of cardiomyocyte proliferation and indicated that lncRNAs take part in the regulation of cardiomyocyte proliferation and cardiac repair. Our study provides an lncRNA-based therapeutic strategy for effective cardiac repair and regeneration.
Assuntos
Proliferação de Células , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Regeneração , Animais , Animais Recém-Nascidos , Sítios de Ligação , Ciclo Celular , Células Cultivadas , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Componente 3 do Complexo de Manutenção de Minicromossomo/genética , Componente 3 do Complexo de Manutenção de Minicromossomo/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Transdução de SinaisRESUMO
Circular RNA (circRNA) is an endogenous noncoding RNA with a covalently closed cyclic structure. Based on their components, circRNAs are divided into exonic circRNAs, intronic circRNAs, and exon-intron circRNAs. CircRNAs have well-conserved sequences and often have high stability due to their resistance to exonucleases. Depending on their sequence, circRNAs are involved in different biological functions, including microRNA sponge activity, modulation of alternative splicing or transcription, interaction with RNA-binding proteins, and rolling translation, and are a derivative of pseudogenes. CircRNAs are involved in the development of a variety of pathological conditions, such as cardiovascular diseases, diabetes, neurological diseases, and cancer. Emerging evidence has shown that circRNAs are likely to be new potential clinical diagnostic markers or treatments for many diseases. Here we describe circRNA research methods and biological functions, and discuss the potential relationship between circRNAs and disease progression.
RESUMO
Reactive oxygen species derived from NADPH oxidase contribute to a wide variety of renal diseases. Nox4, the major NADPH isoform in kidney, produces mainly H2O2 that regulates physiological functions. Nox4 contributes to redox processes involved in diabetic nephropathy, acute kidney injury, obstructive nephropathy, hypertensive nephropathy, renal cell carcinoma and other renal diseases by activating multiple signaling pathways. Although Nox4 is found in a variety of cell types, including epithelial cells, podocytes, mesangial cells, endothelial cells and fibroblasts, its role is not clear and even controversial. In some conditions, Nox4 protects cells by promoting cell survival in response to harmful stimuli. In other scenarios it induces cell apoptosis, inflammation or fibrogenesis. This functional variability may be attributed to distinct cell types, subcellular localization, molecular concentrations, disease type or stage, and other factors yet unexplored. In this setting, we reviewed the function and mechanism of Nox4 in renal diseases, highlighted the contradictions in Nox4 literature, and discussed promising therapeutic strategies targeting Nox4 in the treatment of certain types of renal diseases.
Assuntos
Nefropatias/enzimologia , NADPH Oxidase 4/metabolismo , Animais , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismoRESUMO
Increasing evidence suggests that long noncoding RNAs (lncRNAs) play crucial roles in various biological processes. However, little is known about the effects of lncRNAs on autophagy. Here we report that a lncRNA, termed cardiac autophagy inhibitory factor (CAIF), suppresses cardiac autophagy and attenuates myocardial infarction by targeting p53-mediated myocardin transcription. Myocardin expression is upregulated upon H2O2 and ischemia/reperfusion, and knockdown of myocardin inhibits autophagy and attenuates myocardial infarction. p53 regulates cardiomyocytes autophagy and myocardial ischemia/reperfusion injury by regulating myocardin expression. CAIF directly binds to p53 protein and blocks p53-mediated myocardin transcription, which results in the decrease of myocardin expression. Collectively, our data reveal a novel CAIF-p53-myocardin axis as a critical regulator in cardiomyocyte autophagy, which will be potential therapeutic targets in treatment of defective autophagy-associated cardiovascular diseases.
Assuntos
Autofagia/genética , Infarto do Miocárdio/genética , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , Transativadores/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Camundongos , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Ligação Proteica , Interferência de RNA , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Circular RNAs (circRNAs) have important roles in several cellular processes. No study has established the pathophysiological role for circRNAs in the heart. Here, we show that a circRNA (mitochondrial fission and apoptosis-related circRNA (MFACR)) regulates mitochondrial fission and apoptosis in the heart by directly targeting and downregulating miR-652-3p; this in turn blocks mitochondrial fission and cardiomyocyte cell death by suppressing MTP18 translation. MTP18 deficiency reduces mitochondrial fission and suppresses cardiomyocyte apoptosis and MI. miR-652-3p directly downregulates MTP18 and attenuates mitochondrial fission, cardiomyocyte apoptosis, and MI in vitro and in vivo. MFACR directly sequesters miR-652-3p in the cytoplasm and inhibits its activity. MFACR knockdown in cardiomyocytes and mice attenuates mitochondrial fission and MI. Our results reveal a crucial role for circRNA in regulating mitochondrial dynamics and apoptosis in the heart; as such, circRNAs may serve as a potential therapeutic avenue for cardiovascular diseases.
Assuntos
Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , RNA/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Regulação da Expressão Gênica , Coração , Proteínas de Membrana/genética , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/fisiologia , RNA Circular , Regulação para CimaRESUMO
Doxorubicin (DOX) as a chemotherapeutic drug is widely used to treat a variety of human tumors. However, a major factor limiting its clinical use is its cardiotoxicity. The molecular components and detailed mechanisms regulating DOX-induced cardiotoxicity remain largely unidentified. Here we report that Foxo3a is downregulated in the cardiomyocyte and mouse heart in response to DOX treatment. Foxo3a attenuates DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. Cardiac specific Foxo3a transgenic mice show reduced mitochondrial fission, apoptosis and cardiotoxicity upon DOX administration. Furthermore, Foxo3a directly targets mitochondrial dynamics protein of 49kDa (MIEF2) and suppresses its expression at transcriptional level. Knockdown of MIEF2 reduces DOX-induced mitochondrial fission and apoptosis in cardiomyocytes and in vivo. Also, knockdown of MIEF2 protects heart from DOX-induced cardiotoxicity. Our study identifies a novel pathway composed of Foxo3a and MIEF2 that mediates DOX cardiotoxicity. This discovery provides a promising therapeutic strategy for the treatment of cancer therapy and cardioprotection.
Assuntos
Cardiotoxicidade/genética , Doxorrubicina/efeitos adversos , Proteína Forkhead Box O3/genética , Proteínas Mitocondriais/genética , Neoplasias/complicações , Fatores de Alongamento de Peptídeos/genética , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Doxorrubicina/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.
Assuntos
Fator de Transcrição E2F1/genética , MicroRNAs/genética , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Proteínas Quinases/genética , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Imunoprecipitação da Cromatina , Fator de Transcrição E2F1/metabolismo , Immunoblotting , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica , Mitocôndrias Cardíacas/ultraestrutura , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/ultraestrutura , Proteínas Quinases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
MicroRNAs (miRNAs) are small non-coding RNAs, and they bind to complementary sequences in the three prime untranslated regions (3' UTRs) of target mRNA transcripts, thereby inhibiting mRNA translation or promoting mRNA degradation. Excessive reactive oxygen species (ROS) can cause cell-damaging effects through oxidative modification of macromolecules leading to their inappropriate functions. Such oxidative modification is related to cancers, aging, and neurodegenerative and cardiovascular diseases. Here we report that miRNAs can be oxidatively modified by ROS. We identified that miR-184 upon oxidative modification associates with the 3' UTRs of Bcl-xL and Bcl-w that are not its native targets. The mismatch of oxidized miR-184 with Bcl-xL and Bcl-w is involved in the initiation of apoptosis in the study with rat heart cell line H9c2 and mouse models. Our results reveal a model of ROS in regulating cellular events by oxidatively modifying miRNA.
Assuntos
Regiões 3' não Traduzidas/genética , MicroRNAs/metabolismo , Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Proteína bcl-X/genética , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/citologia , Miocárdio/metabolismo , Oxirredução , Interferência de RNA , RNA Interferente Pequeno , RatosRESUMO
RATIONALE: Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently. OBJECTIVE: The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1- and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD. METHODS AND RESULTS: Our results show that FADD participates in H2O2-induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR-103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouse ischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor-α-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis. CONCLUSIONS: Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR-103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis.
Assuntos
Proteína de Domínio de Morte Associada a Fas/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteína de Domínio de Morte Associada a Fas/genética , Células HEK293 , Humanos , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Necrose , Oligonucleotídeos/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Transfecção , Fator de Necrose Tumoral alfa/toxicidadeRESUMO
Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. T-cell immunoglobulin and ITIM domain (TIGIT) receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/poliovirus receptor (PVR) ligand engagement signaling inhibits cytotoxicity mediated by NK and CD8(+) T cells. However, it is unclear how TIGIT/PVR signaling regulates cytokine secretion in NK cells. Here we show that TIGIT/PVR engagement suppresses interferon-γ (IFN-γ) production of NK cells. TIGIT transgenic NK cells generate less IFN-γ undergoing TIGIT/PVR ligation. Moreover, TIGIT knock-out NK cells produce much more IFN-γ. TIGIT/PVR ligation signaling mediates suppression of IFN-γ production via the NF-κB pathway. We identified a novel adaptor ß-arrestin 2 that associates with phosphorylated TIGIT for further recruitment of SHIP1 (SH2-containing inositol phosphatase 1) through the ITT-like motif. Importantly, SHIP1, but not other phosphatases, impairs the TNF receptor-associated factor 6 (TRAF6) autoubiquitination to abolish NF-κB activation, leading to suppression of IFN-γ production in NK cells.
Assuntos
Arrestinas/metabolismo , Interferon gama/biossíntese , Células Matadoras Naturais/metabolismo , Receptores Imunológicos/metabolismo , Receptores Virais/metabolismo , Transdução de Sinais/fisiologia , Animais , Arrestinas/genética , Arrestinas/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Humanos , Capeamento Imunológico/fisiologia , Inositol Polifosfato 5-Fosfatases , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/imunologia , Monoéster Fosfórico Hidrolases/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Virais/genética , Receptores Virais/imunologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , beta-Arrestina 2 , beta-ArrestinasRESUMO
Cardiac hypertrophic program is a chronic, complex process, and occurs in response to long-term increases of hemodynamic load related to a variety of pathophysiological conditions. Mitochondria, known as "the cellular power plants", occupy about one-third of cardiomyocyte volume and supply roughly 90% of the adenosine triphosphate (ATP). Impairment of energy metabolism has been regarded as one of the main pathogenesis of cardiac hypertrophy. Thus, we summarize here the molecular events of mitochondrial adaptations, including the mitochondrial genesis, ATP generation, ROS signaling and Ca(2+) homeostasis in cardiac hypertrophy, expecting that this effort will shed new light on understanding the maladaptive cardiac remodeling.