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Paternal dietary conditions may contribute to metabolic disorders in offspring. We have analyzed the role of the stress-dependent epigenetic regulator cyclic AMP-dependent transcription factor 7 (ATF7) in paternal low-protein diet (pLPD)-induced gene expression changes in mouse liver. Atf7+/- mutations cause an offspring phenotype similar to that caused by pLPD, and the effect of pLPD almost vanished when paternal Atf7+/- mice were used. ATF7 binds to the promoter regions of â¼2,300 genes, including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). LPD induces ATF7 phosphorylation by p38 via reactive oxygen species (ROS) in TGCs. This leads to the release of ATF7 and a decrease in histone H3K9 dimethylation (H3K9me2) on its target genes. These epigenetic changes are maintained and induce expression of some tRNA fragments in spermatozoa. These results indicate that LPD-induced and ATF7-dependent epigenetic changes in TGCs play an important role in paternal diet-induced metabolic reprograming in offspring.
Assuntos
Fatores Ativadores da Transcrição/genética , Dieta com Restrição de Proteínas , Epigênese Genética , Fígado/fisiologia , Espermatozoides/fisiologia , Fatores Ativadores da Transcrição/metabolismo , Animais , Feminino , Regulação da Expressão Gênica , Histonas/metabolismo , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Fosforilação , Regiões Promotoras GenéticasRESUMO
Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, including the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential for regulating neural stem cells in developing, adult and aged brains. However, the activity of these lysosomes has yet to be monitored in these brain tissues. Here, we report the development of a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results indicate that lysosomal protein degradation fluctuates in neural stem cells of the hippocampal dentate gyrus, depending on age and brain disorders. Neural stem cells increase their lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduce lysosomal activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes in the dentate gyrus. We therefore propose that three different stages of lysosomal activity exist: the state of increase during development, the stable state during adulthood and the state of reduction due to damage caused by either age or disease.
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Giro Denteado , Células-Tronco Neurais , Animais , Camundongos , Giro Denteado/metabolismo , Proteólise , Células-Tronco Neurais/metabolismo , Astrócitos/metabolismo , Lisossomos/metabolismoRESUMO
Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcription factor ATF7 in innate immunological memory. ATF7 suppressed a group of genes encoding factors involved in innate immunity in macrophages by recruiting the histone H3K9 dimethyltransferase G9a. Treatment with lipopolysaccharide, which mimics bacterial infection, induced phosphorylation of ATF7 via the kinase p38, which led to the release of ATF7 from chromatin and a decrease in repressive histone H3K9me2 marks. A partially disrupted chromatin structure and increased basal expression of target genes were maintained for long periods, which enhanced resistance to pathogens. ATF7 might therefore be important in controlling memory in cells of the innate immune system.
Assuntos
Fatores Ativadores da Transcrição/metabolismo , Epigênese Genética/imunologia , Memória Imunológica/genética , Memória Imunológica/imunologia , Macrófagos/imunologia , Fatores Ativadores da Transcrição/genética , Animais , Epigênese Genética/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Atf1, the fission yeast homolog of activation transcription factor-2 (ATF-2), contributes to heterochromatin formation. However, the role of ATF-2 in chromatin assembly in higher organisms remains unknown. This study reveals that Drosophila ATF-2 (dATF-2) is required for heterochromatin assembly, whereas the stress-induced phosphorylation of dATF-2, via Mekk1-p38, disrupts heterochromatin. The dATF-2 protein colocalized with HP1, not only on heterochromatin but also at specific loci in euchromatin. Heat shock or osmotic stress induced phosphorylation of dATF-2 and resulted in its release from heterochromatin. This heterochromatic disruption was an epigenetic event that was transmitted to the next generation in a non-Mendelian fashion. When embryos were exposed to heat stress over multiple generations, the defective chromatin state was maintained over multiple successive generations, though it gradually returned to the normal state. The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure.
Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/genética , Heterocromatina/metabolismo , Fator 2 Ativador da Transcrição/análise , Fator 2 Ativador da Transcrição/genética , Animais , Proteínas de Drosophila/análise , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Epigenômica , Eucromatina/metabolismo , Feminino , Heterocromatina/química , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , Mutagênese , Fosforilação , Transdução de Sinais , Estresse Fisiológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The endosomal-lysosomal system represents a crucial degradation pathway for various extracellular substances, and its dysfunction is linked to cardiovascular and neurodegenerative diseases. This degradation process involves multiple steps: (1) the uptake of extracellular molecules, (2) transport of cargos to lysosomes, and (3) digestion by lysosomal enzymes. While cellular uptake and lysosomal function are reportedly regulated by the mTORC1-TFEB axis, the key regulatory signal for cargo transport remains unclear. Notably, our previous study discovered that isorhamnetin, a dietary flavonoid, enhances endosomal-lysosomal proteolysis in the J774.1 cell line independently of the mTORC1-TFEB axis. This finding suggests the involvement of another signal in the mechanism of isorhamnetin. This study analyzes the molecular mechanism of isorhamnetin using transcriptome analysis and reveals that the transcription factor GATA3 plays a critical role in enhanced endosomal-lysosomal degradation. Our data also demonstrate that mTORC2 regulates GATA3 nuclear translocation, and the mTORC2-GATA3 axis alters endosomal formation and maturation, facilitating the efficient transport of cargos to lysosomes. This study suggests that the mTORC2-GATA3 axis might be a novel target for the degradation of abnormal substances.
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Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated the effect of HIF-PH inhibitors in patients with HF and CKD. Materials and Methods: Thirteen patients with HF complicated by renal anemia who were started on vadadustat were enrolled. Clinical parameters were compared before and 1 month after vadadustat was started. Results: The mean left ventricular ejection fraction was 49.8 ± 13.9%, and the mean estimated glomerular filtration rate was 29.4 ± 10.6 mL/min/1.73 m2. The hemoglobin level was significantly increased (9.7 ± 1.3 mg/dL vs. 11.3 ± 1.3 mg/dL, p < 0.001), and the N-terminal prohormone of B-type natriuretic peptide was significantly decreased after the introduction of vadadustat [4357 (2651-15182) pg/mL vs. 2367 (1719-9347) pg/mL, p = 0.002]. Furthermore, the number of patients with New York Heart Association functional class ≥ 3 was also decreased after the introduction of vadadustat [8 (61.5%) vs. 1 (7.7%), p = 0.008]. No thromboembolic adverse events or new tumors were observed in any patient during the study period. Conclusions: The introduction of vadadustat in patients with HF complicated by renal anemia led to improvements in anemia and symptoms of HF.
Assuntos
Anemia , Insuficiência Cardíaca , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Tromboembolia , Humanos , Prolil Hidroxilases , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/uso terapêutico , Volume Sistólico , Função Ventricular Esquerda , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/etiologia , HipóxiaRESUMO
BACKGROUND: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. METHODS: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. RESULTS: 44 patients (median (interquartile range) age 39 (29-57)â years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40â mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514â dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. CONCLUSIONS: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Estenose de Artéria Pulmonar , Adulto , Feminino , Humanos , Criança , Estenose de Artéria Pulmonar/diagnóstico por imagem , Estenose de Artéria Pulmonar/terapia , Hipertensão Pulmonar/terapia , Constrição Patológica , Artéria Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar Primária Familiar/tratamento farmacológicoRESUMO
Despite previous studies showing that patients with low systolic blood pressure (sBP) in heart failure with reduced ejection fraction (HFrEF) has a poor prognosis, it has few treatment options. This study aimed to investigate the efficacy and safety of sacubitril/valsartan (S/V) in HFrEF patients with hypotension. We included 43 consecutive HFrEF patients with sBP < 100 mmHg despite guideline-directed medical therapy for at least 3 months and who received S/V between September 2020 and July 2021. Patients admitted for acute heart failure were excluded and 29 patients were evaluated for safety endpoints. Furthermore, patients who performed non-pharmacological therapy or died within 1 month were excluded, finally, 25 patients were evaluated for efficacy endpoints. The mean initial S/V dose was 53.0 ± 20.5 mg/day and the mean dosage was increased to 84.0 ± 34.5 mg/day in 1 month. Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values significantly decreased from 2200 [interquartile range (IQR): 1462-3666] pg/ml to 1409 (IQR: 964-2451) pg/ml. (p < 0.0001). No significant change in sBP occurred (pre-sBP: 93.2 ± 4.9 mmHg, post-sBP: 93.4 ± 9.6 mmHg, p = 0.91), and no patients discontinued the S/V due to symptomatic hypotension in 1 month after S/V initiation. S/V can be safely introduced in HFrEF patients with hypotension to reduce serum NT-proBNP values. Thus, S/V may be useful for the treatment of HFrEF patients with hypotension.
Assuntos
Insuficiência Cardíaca , Hipotensão , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Tetrazóis/efeitos adversos , Valsartana/uso terapêutico , Hipotensão/induzido quimicamente , Combinação de MedicamentosRESUMO
Mitochondria are essential organelles that carry out a number of pivotal metabolic processes and maintain cellular homeostasis. Mitochondrial dysfunction caused by various stresses is associated with many diseases such as type 2 diabetes, obesity, cancer, heart failure, neurodegenerative disorders, and aging. Therefore, it is important to understand the stimuli that induce mitochondrial stress. However, broad analysis of mitochondrial stress has not been carried out to date. Here, we present a set of fluorescent tools, called mito-Pain (mitochondrial PINK1 accumulation index), which enable the labeling of stressed mitochondria. Mito-Pain uses PTEN-induced putative kinase 1 (PINK1) stabilization on mitochondria and quantifies mitochondrial stress levels by comparison with PINK1-GFP, which is stabilized under mitochondrial stress, and RFP-Omp25, which is constitutively localized on mitochondria. To identify compounds that induce mitochondrial stress, we screened a library of 3374 compounds using mito-Pain and identified 57 compounds as mitochondrial stress inducers. Furthermore, we classified each compound into several categories based on mitochondrial response: depolarization, mitochondrial morphology, or Parkin recruitment. Parkin recruitment to mitochondria was often associated with mitochondrial depolarization and aggregation, suggesting that Parkin is recruited to heavily damaged mitochondria. In addition, many of the compounds led to various mitochondrial morphological changes, including fragmentation, aggregation, elongation, and swelling, with or without Parkin recruitment or mitochondrial depolarization. We also found that several compounds induced an ectopic response of Parkin, leading to the formation of cytosolic puncta dependent on PINK1. Thus, mito-Pain enables the detection of stressed mitochondria under a wide variety of conditions and provides insights into mitochondrial quality control systems.
Assuntos
Fluorescência , Corantes Fluorescentes/química , Mitocôndrias/enzimologia , Proteínas Mitocondriais/metabolismo , Proteínas Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Estresse Fisiológico , Animais , Células COS , Chlorocebus aethiops , Estabilidade Enzimática , Células HEK293 , Células HeLa , Humanos , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Proteínas Quinases/genéticaRESUMO
BACKGROUND: Clinical predictors for successful weaning of patients from Impella heart pump have not been clarified. We aimed to elucidate the relationship between pulmonary artery catheter (PAC) parameters at the time of Impella weaning and subsequent outcomes. METHODS: We enrolled consecutive patients who had received Impella for cardiogenic shock. PAC data were collected immediately before Impella weaning. Patients were classified as non-survivors if they died or required any mechanical circulatory support reintroduction within 30 days of weaning. RESULTS: Of 81 patients enrolled, 61 underwent Impella weaning. Of these, 16 were non-survivors. Predictive indicators of non-survival were high pulmonary artery wedge pressure (PAWP; hazard ratio [HR] per 5 mm Hg 1.97, 95% CI 1.35-2.80; p < 0.001), high mean pulmonary artery pressure (MPAP; HR per 5 mm Hg 1.90, 1.38-2.58; p < 0.001), and low cardiac power output (CPO; HR per 0.1 Watts 0.71, 0.52-0.92; p = 0.006). Cutoff values of PAWP 20 mm Hg, MPAP 22 mm Hg, and CPO 0.59 Watts showed strong associations with 30-day non-survival risk (low risk 8% in patients with low PAWP and high CPO or 4% in patients with low MPAP and high CPO; high risk 100% in patients with high PAWP and low CPO or 82% in patients with high MPAP and low CPO). CONCLUSIONS: PAWP or MPAP higher than the cutoff with CPO below the cutoff at Impella weaning were associated with worse outcomes. We proposed a risk classification model for successful Impella weaning using PAC.
Assuntos
Coração Auxiliar , Choque Cardiogênico , Coração Auxiliar/efeitos adversos , Hemodinâmica , Humanos , Estudos Retrospectivos , Choque Cardiogênico/etiologia , Choque Cardiogênico/cirurgia , Resultado do Tratamento , DesmameRESUMO
Although autophagy is classically viewed as a non-selective degradation system, recent studies have revealed that various forms of selective autophagy also play crucial physiological roles. However, the induction of selective autophagy is not well understood. In this study, we established a forced selective autophagy system using a fusion of an autophagy adaptor and a substrate-binding protein. In both mammalian cells and fertilized mouse embryos, efficient forced lipophagy was induced by expression of a fusion of p62 (Sqstm1) and a lipid droplet (LD)-binding domain. In mouse embryos, induction of forced lipophagy caused a reduction in LD size and number, and decreased the triglyceride level throughout embryonic development, resulting in developmental retardation. Furthermore, lipophagy-induced embryos could eliminate excess LDs and were tolerant of lipotoxicity. Thus, by inducing forced lipophagy, expression of the p62 fusion protein generated LD-depleted cells, revealing an unexpected role of LD during preimplantation development.
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Autofagia/fisiologia , Desenvolvimento Embrionário/fisiologia , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Animais , Técnicas de Cultura de Células , Citometria de Fluxo , Immunoblotting , Lipólise/fisiologia , Camundongos , Microscopia de Fluorescência , Perilipina-3/metabolismoRESUMO
Clinical parameters with correlation to diuretic effects after initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors are unclear. We aimed to identify the factors associated with the diuretic effect observed following the initiation of SGLT2 inhibitors in patients with diabetes having an acute heart failure (HF). Fifty-six patients included were hospitalized for acute HF with diabetes and started on SGLT2 inhibitors. Changes in urine volume (ΔUV) and blood/urine laboratory parameters before and during the first 4 days of therapy were evaluated. Data were prospectively obtained under clinically stable conditions after initial HF treatment. UV increased following the initiation of SGLT2 inhibitors [UV at baseline (BL): 1383 ± 479 mL/day; ΔUV over 4 days: + 189 ± 358 mL/day]. Multivariate analysis revealed no association between BL-hemoglobin A1c or BL-estimated glomerular filtration rate and ΔUV. Conversely, higher BL-fasting plasma glucose (FPG) and higher BL-urine N-acetyl-ß-D-glucosaminidase (NAG) were associated with a higher ΔUV. ΔUV was inversely associated with ΔFPG and ΔNAG, and positively associated with Δurinary sodium excretion. Elevated FPG and NAG both improved over 4 days of treatment. In conclusion, the diuretic effect of SGLT2 inhibitors was glycemia-dependent, and was associated with a reduction in elevated renal-tubular markers in hospitalized HF complicated with diabetes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Doença Aguda , Biomarcadores/sangue , Biomarcadores/urina , Diabetes Mellitus/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Insuficiência Cardíaca/metabolismo , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sódio/urinaRESUMO
Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.
Assuntos
Fatores Ativadores da Transcrição/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Transcrição Gênica , Fator de Necrose Tumoral alfa/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Cromatina/genética , Heterocromatina/genética , Humanos , Camundongos , Fosforilação , Regiões Promotoras Genéticas , Estresse Psicológico , Telômero/genética , Encurtamento do Telômero/genéticaRESUMO
Cellular senescence plays an important role in aging and is induced by cyclin-dependent kinase (Cdk) inhibitors that accumulate following stresses during aging. However, the underlying mechanism remains elusive. Herein, we demonstrate that activating transcription factor 7 (ATF7), the stress-responsive recruiter of histone H3K9 di- and trimethyltransferases, functions in the accumulation of Cdk inhibitors. Atf7-deficient (Atf7-/- ) mice have a shorter lifespan than wild-type (WT) mice. Levels of p16Ink4a Cdk inhibitor mRNA increased with age more rapidly in Atf7-/- mice than in WT animals. ATF7 binds to the p16Ink4a gene promoter and was released with age. Consistently, histone H3K9me2 levels on the p16Ink4a gene promoter were lower in Atf7-/- mice than in WT animals. Similar results were obtained when Atf7-/- and WT mouse embryonic fibroblasts (MEFs) were cultured under 20% oxygen conditions, which induces cellular senescence via oxidative stress. Phosphorylation of ATF7 by p38 was also increased with the passage of MEFs, consistent with previous observations that ATF7 phosphorylation by p38 induces its release from chromatin. These results indicate that stress-induced and ATF7-dependent epigenetic changes on p16Ink4a genes play an important role in cellular senescence.
Assuntos
Fatores Ativadores da Transcrição/metabolismo , Senescência Celular , Epigênese Genética , Estresse Oxidativo , Fatores Ativadores da Transcrição/genética , Animais , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Histonas/genética , Histonas/metabolismo , Longevidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Integrated device diagnostics, Triage-HF, is useful in risk stratifying patients with heart failure (HF), but its performance for Japanese patients remains unknown. This is a prospective study of Japanese patients treated with a cardiac resynchronization therapy defibrillator (CRT-D), with a Medtronic OptiVol 2.0 feature.MethodsâandâResults:A total of 320 CRT-D patients were enrolled from 2013 to 2017. All received HF treatment in the prior 12 months. Following enrollment, they were followed every 6 months for 48 months (mean, 22 months). Triage-HF-stratified patients at low, medium and high risk statuses at every 30-day period, and HF-related hospitalization occurring for the subsequent 30 days, were evaluated and repeated. The primary endpoint was to assess Triage-HF performance in predicting HF-related hospitalization risk. All device data were available for 279 of 320 patients (NYHA class II or III in 93%; mean left ventricular ejection fraction, 31%). During a total of 5,977 patient-month follow-ups, 89 HF-related hospitalization occurred in 72 patients. The unadjusted event numbers for Low, Medium and High statuses were 19 (0.7%), 42 (1.6%) and 28 (4.1%), respectively. Relative risk of Medium to Low status was 2.18 (95% CI 1.23-3.85) and 5.78 (95% CI 3.34-10.01) for High to Low status. Common contributing factors among the diagnostics included low activity, OptiVol threshold crossing, and elevated night heart rate. CONCLUSIONS: Triage-HF effectively stratified Japanese patients at risk of HF-related hospitalization.
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Algoritmos , Dispositivos de Terapia de Ressincronização Cardíaca , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/diagnóstico , Telemetria/instrumentação , Idoso , Idoso de 80 Anos ou mais , Feminino , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Hospitalização , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Vigilância de Produtos Comercializados , Estudos Prospectivos , Medição de Risco , Resultado do Tratamento , TriagemRESUMO
Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-α-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-α, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.
Assuntos
Fatores Ativadores da Transcrição/fisiologia , Encurtamento do Telômero , Fator de Necrose Tumoral alfa/fisiologia , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Animais , Fibroblastos , Células HeLa , Histonas/metabolismo , Humanos , Autoantígeno Ku/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Telomerase/metabolismo , Telômero/metabolismoRESUMO
Re-worsening left ventricular ejection fraction (LVEF) is observed in some patients with dilated cardiomyopathy (DCM) despite initial improvements in LVEF. We analyzed cardiac outcomes and clinical variables associated with this re-worsening LVEF. A total of 180 newly diagnosed DCM patients who received only pharmacotherapy were enrolled. Echocardiography was performed after 6, 12, 24, and 36 months after initiation of pharmacotherapy. Patients were divided into three groups: (1) Improved: (n = 113, 63%), defined as those > 10% increase in LVEF after 12 months and no decrease (> 10%) between 12 and 36 months; (2) Re-worse: (n = 12, 7%), those with > 10% increase in LVEF after 12 months but with decrease (> 10%) between 12 and 36 months; and (3) Not-improved: (n = 55: 30%), those with no increase in LVEF (> 10%) after 12 months. Patients with re-worse group were older (P = 0.04) and had higher brain natriuretic peptide (BNP) levels after 12 months (P = 0.002) than those in the Improved group. Major cardiac events (sudden death, implantation of a ventricular assist device, and death due to heart failure,) were observed in 13 (7%) patients after 36 months of pharmacotherapy. Multivariate analysis revealed that the Re-worse group had a higher risk for cardiac events (hazard ratio 11.7, 95% confidence interval 1.9-90.7, P = 0.01) than the Improved group, but had a similar risk compared with the Not-improved group. Re-worsening LVEF was associated with poor cardiac outcomes in newly diagnosed DCM patients. Age and persistently high-BNP levels after improvement in LVEF were significantly associated with re-worsening LVEF.
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Cardiomiopatia Dilatada/fisiopatologia , Ventrículos do Coração/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/terapia , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Coração Auxiliar , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
The variant histones TH2A and TH2B are abundant in the testis, but their roles in spermatogenesis remain elusive. Here, we show that male mutant mice lacking both Th2a and Th2b genes were sterile, with few sperm in the epididymis. In the mutant testis, the lack of TH2B was compensated for by overexpression of H2B, whereas overexpression of H2A was not observed, indicating a decrease in the total histone level. Mutant mice exhibited two defects: incomplete release of cohesin at interkinesis after meiosis I and histone replacement during spermiogenesis. In the mutant testis, secondary spermatocytes at interkinesis accumulated and cohesin was not released normally, suggesting that the retained cohesion of sister chromatids delayed the subsequent entry into meiosis II. In addition, impaired chromatin incorporation of TNP2 and degenerated spermatids were observed in the mutant testis. These results suggest that a loss of TH2A and TH2B function in chromatin dynamics or a decrease in the total histone levels causes defects in both cohesin release and histone replacement during spermatogenesis.
Assuntos
Deleção de Genes , Histonas/genética , Espermatogênese/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos de Mamíferos/metabolismo , Proteínas de Ligação a DNA , Feminino , Histonas/deficiência , Histonas/metabolismo , Masculino , Meiose , Camundongos Endogâmicos BALB C , Mutação/genética , Proteínas Nucleares/metabolismo , Espermátides/citologia , Espermátides/metabolismo , Espermatócitos/citologia , Espermatócitos/metabolismo , Testículo/citologia , Testículo/metabolismo , CoesinasRESUMO
An interaction between the intestine and cardiovascular disease has been suggested. We thought to clarify the association between intestinal conditions and clinical outcomes in patients with heart failure (HF). Hemodynamic parameters in intestinal vessels [superior mesenteric artery (SMA), inferior mesenteric artery (IMA), and portal vein (PV)] and average colon wall thickness (aCWT) from the ascending colon to sigmoid colon were evaluated in 224 hospitalized HF patients. Echocardiographic parameters and composite event rates (all-cause mortality, readmission for HF deterioration, major ventricular arrhythmias) were also examined. Higher PV congestion index (CI) and aCWT were observed in patients with New York Heart Association (NYHA) class III/IV. Higher PVCI [hazard ratio (HR) per + 1 standard deviation (SD) 1.50, p < 0.01] and aCWT (HR per + 1 SD 1.45, p < 0.01) were independently associated with higher composite event rates during the follow-up of 122 ± 68 days. None of SMA/IMA hemodynamic parameters were associated with NYHA class or composite event rates. Higher right ventricular end-diastolic dimension (38 ± 7 vs 34 ± 9 mm, p < 0.01) and lower tricuspid annual plane systolic excursion (15 ± 5 vs 19 ± 5 mm, p < 0.001) were observed in patients with higher PVCI (> 0.031 cm s) and aCWT (> 2.8 mm) relative to those in others. In conclusion, increased portal congestion and intestinal edema were associated with severe HF symptoms and poor outcomes in hospitalized HF patients, in addition to being associated with impaired right-sided cardiac function.
Assuntos
Edema/etiologia , Insuficiência Cardíaca/complicações , Hipertensão Portal/etiologia , Pacientes Internados , Enteropatias/etiologia , Veia Porta/fisiopatologia , Idoso , Ecocardiografia , Edema/diagnóstico , Edema/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Hipertensão Portal/fisiopatologia , Enteropatias/diagnóstico , Enteropatias/fisiopatologia , Masculino , Prognóstico , Estudos Prospectivos , Volume Sistólico , Ultrassonografia , Função Ventricular EsquerdaRESUMO
Decongestion is an important goal of heart failure (HF) management. Blood cell concentration is a recognized indicator for guiding decongestive treatment for HF. We aimed to assess the clinical impact of hemodilution and hemoconcentration after initial treatment in acute decompensated HF (ADHF) patients. We retrospectively evaluated hemoglobin levels and body weight obtained before admission, on admission, 3 days after admission, and at discharge in 102 consecutive patients admitted with ADHF. Patients were then stratified into hemodilution (n = 55) and hemoconcentration (n = 47) groups based on whether their hemoglobin levels decreased or increased, respectively, during the first 3 days after admission. From before admission to admission, hemoglobin levels decreased less in the hemodilution group (-0.16 ± 0.98 g/dL) than in the hemoconcentration group (-0.88 ± 1.11 g/dL) (P < 0.001); however, there was no significant difference in body weight (P≥ 0.05). More patients in the hemodilution group (85%) had grade III/IV pulmonary edema (Turner's criteria) compared with the hemoconcentration group (63%) (P < 0.01). Rate of readmission for HF within 180 days of discharge was higher in the hemodilution group (34%) compared with the hemoconcentration group (9%) (P < 0.01). Hemodilution after initial treatment for ADHF was associated with severe pulmonary edema at admission and higher readmission rates.