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1.
Circ Res ; 108(4): 437-45, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21233454

RESUMO

RATIONALE: Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling. OBJECTIVE: To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts. METHODS AND RESULTS: We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice. Calcineurin-dependent transcript levels and nuclear occupancy of the NFAT (nuclear factor of activated T cells) regularly fluctuated as much as 20-fold over the course of a day, peaking in the morning when mice enter a period of rest. Phosphorylation of the protein phosphatase 1 inhibitor 1 (I-1), a direct calcineurin substrate, and phospholamban, an indirect target, oscillated directly out of phase with calcineurin-dependent signaling. Using a surgical model of cardiac pressure overload, we found that although calcineurin-dependent activities were markedly elevated, the circadian pattern of activation was maintained, whereas, oscillations in phospholamban and I-1 phosphorylation were lost. Changes in the expression of fetal gene markers of heart failure did not mirror the rhythm in calcineurin/NFAT activation, suggesting that these may not be direct transcriptional target genes. Cardiac function in mice subjected to pressure overload was significantly lower in the morning than in the evening when assessed by echocardiography. CONCLUSIONS: Normal, opposing circadian oscillations in calcineurin-dependent activities and phosphorylation of proteins that regulate contractility are disrupted in heart failure.


Assuntos
Calcineurina/fisiologia , Ritmo Circadiano/fisiologia , Insuficiência Cardíaca/metabolismo , Hemodinâmica/fisiologia , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Estresse Fisiológico/fisiologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fosforilação/fisiologia , Proteína Fosfatase 1/metabolismo
2.
Circ Res ; 106(2): 272-84, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20133912

RESUMO

Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-to-mesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Animais , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/prevenção & controle , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/prevenção & controle , Modelos Biológicos
4.
Mol Cell Biol ; 24(24): 10636-49, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15572669

RESUMO

Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.


Assuntos
Cardiomegalia/metabolismo , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Carioferinas/metabolismo , Miócitos Cardíacos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Adenoviridae/genética , Adenilato Quinase/análise , Adenilato Quinase/metabolismo , Adesinas Bacterianas/metabolismo , Adesinas Bacterianas/farmacologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/metabolismo , Fator Natriurético Atrial/análise , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/fisiologia , Cardiomegalia/genética , Tamanho Celular , Sobrevivência Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Fluoresceínas , Corantes Fluorescentes , Proteínas de Fluorescência Verde/metabolismo , Ventrículos do Coração/citologia , Histona Desacetilases/metabolismo , Immunoblotting , Carioferinas/antagonistas & inibidores , Carioferinas/farmacologia , Microscopia de Fluorescência , Miócitos Cardíacos/citologia , Testes de Precipitina , RNA/análise , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Ativação Transcricional , Proteína Exportina 1
5.
Expert Opin Ther Targets ; 13(7): 767-84, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19466913

RESUMO

BACKGROUND: Stresses such as chronic hypertension and myocardial infarction can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Recent studies suggest key roles for histone deacetylases (HDACs) in the control of pathological cardiac remodeling. OBJECTIVE/METHODS: Here, we review these target validation experiments and highlight non-cardiac functions of HDACs that will need to be addressed during development of HDAC-directed therapies for heart failure. RESULTS/CONCLUSIONS: HDACs are unique and attractive therapeutic targets for heart failure because of their positions far downstream in pathological signaling cascades. Confirmation of the validity and viability of approaches aimed at HDACs awaits in vivo proof-of-concept testing with novel small molecule regulators of these enzymes.


Assuntos
Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Histona Desacetilases , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Insuficiência Cardíaca/fisiopatologia , Histona Desacetilases/metabolismo , Humanos , Remodelação Ventricular/efeitos dos fármacos
6.
Development ; 133(10): 2001-10, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16651542

RESUMO

The final step in Hedgehog (Hh) signal transduction is post-translational regulation of the transcription factor, Cubitus interruptus (Ci). Ci resides in the cytoplasm in a latent form, where Hh regulates its processing into a transcriptional repressor or its nuclear access as a transcriptional activator. Levels of latent Ci are controlled by degradation, with different pathways activated in response to different levels of Hh. Here, we describe the roadkill (rdx) gene, which is expressed in response to Hh. The Rdx protein belongs to a conserved family of proteins that serve as substrate adaptors for Cullin3-mediated ubiquitylation. Overexpression of rdx reduced Ci levels and decreased both transcriptional activation and repression mediated by Ci. Loss of rdx allowed excessive accumulation of Ci. rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells. These studies identify rdx as a limiting factor in a feedback loop that attenuates Hh responses through reducing levels of Ci. The existence of human orthologs for Rdx raises the possibility that this novel feedback loop also modulates Hh responses in humans.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Insetos/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Alelos , Animais , Mapeamento Cromossômico , Cromossomos , Proteínas de Ligação a DNA/genética , Drosophila/embriologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Embrião não Mamífero , Olho/citologia , Olho/embriologia , Olho/ultraestrutura , Genes de Insetos , Proteínas Hedgehog , Proteínas de Insetos/genética , Modelos Biológicos , Fatores de Transcrição/genética , Transgenes
7.
J Biol Chem ; 281(44): 33487-96, 2006 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-16950785

RESUMO

The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart.


Assuntos
Calcineurina/metabolismo , Cardiomegalia/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/metabolismo , Anilidas/farmacologia , Animais , Cardiomegalia/genética , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , Fatores de Transcrição NFATC/metabolismo , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/genética , Tiadiazóis/farmacologia
8.
Proc Natl Acad Sci U S A ; 101(9): 2870-5, 2004 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-14976250

RESUMO

The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT(2A/2B) receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. These findings identify MCIP1 as a downstream target of 5-HT(2A/2B) receptor signaling in cardiac muscle cells and suggest possible uses for 5-HT(2A/2B) agonists and antagonists as modulators of cardiac growth and gene expression.


Assuntos
Inibidores de Calcineurina , Calcineurina/fisiologia , Cardiomegalia/genética , Regulação da Expressão Gênica/genética , Coração/fisiologia , Proteínas Musculares/genética , Animais , Animais Recém-Nascidos , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/farmacologia , Transdução de Sinais , Transcrição Gênica , Transfecção
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