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PURPOSE: One way of evaluating family history (FH) for classifying BRCA1/2 variants of uncertain clinical significance (VUS) is to assess the "BRCA-ness" of a pedigree by comparing it to reference populations. The aim of this study was to assess if prediction of BRCA pathogenic variant (mutation) status based on pedigree information differed due to changes in FH since intake, both in families with a pathogenic variant (BRCAm) and in families with wild-type (BRCAwt). PATIENTS AND METHODS: We compared the BRCA1/2 pathogenic variant detection probabilities between intake and most recent pedigree for BRCAm families (n = 64) and BRCAwt (n = 118) using the BRCAPRO software program. RESULTS: Follow-up time between intake and most recent pedigree was significantly longer (p < 0.001) in the BRCAm compared to the BRCAwt families. Among BRCAwt families, the probability to detect a pathogenic variant did not change over time. Conversely, among the BRCAm, this probability was significantly higher for most recent vs. intake pedigree (p = 0.006). CONCLUSION: Clinical scores change significantly over time for BRCAm families. This may be due to differences in follow-up, but also to differences in cancer risks from carrying a pathogenic variant in a highly penetrant gene. To reduce bias, models for VUS classification should incorporate FH collected at intake.
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BACKGROUND: Alterations in serotonergic (5-HT) metabolism and/or intestinal integrity have been associated with irritable bowel syndrome (IBS). AIMS: To assess the effects of the precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on mucosal 5-HT availability and intestinal integrity, and to assess potential differences between healthy controls and IBS patients. METHODS: Fifteen IBS patients and 15 healthy volunteers participated in this randomised double-blind placebo-controlled study. Intestinal integrity was assessed by dual-sugar test and by determining the mucosal expression of tight junction proteins after ingestion of an oral bolus of 100 mg 5-HTP or placebo. Mucosal serotonergic metabolism was assessed in duodenal biopsy samples. RESULTS: 5-HTP administration significantly increased mucosal levels of 5-HIAA, the main metabolite of 5-HT, in both healthy controls (7.1 ± 1.7 vs. 2.5 ± 0.7 pmol/mg, 5-HTP vs. placebo, P = 0.02) and IBS patients (20.0 ± 4.8 vs. 8.1 ± 1.3 pmol/mg, 5-HTP vs. placebo, P = 0.02), with the latter group showing a significantly larger increase. Lactulose/L-rhamnose ratios were significantly lower after administration of 5-HTP (P < 0.05) in healthy controls and were accompanied by redistribution of zonula occludens-1 (ZO-1), pointing to reinforcement of the barrier. In IBS, expression of the tight junction proteins was significantly lower compared to healthy controls, and 5-HTP resulted in a further decrease in occludin expression. CONCLUSIONS: Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.
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Mucosa Intestinal/patologia , Intestinos/fisiopatologia , Síndrome do Intestino Irritável/fisiopatologia , Serotonina/metabolismo , 5-Hidroxitriptofano/administração & dosagem , 5-Hidroxitriptofano/farmacologia , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Ácido Hidroxi-Indolacético/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Junções Íntimas/metabolismo , Adulto JovemRESUMO
Oxidative phosphorylation disorders are often associated with increased oxidative stress and antioxidant therapy is frequently given as treatment. However, the role of oxidative stress in oxidative phosphorylation disorders or patients is far from clear and consequently the preventive or therapeutic effect of antioxidants is highly anecdotic. Therefore, we performed a systematic study of a panel of oxidative stress parameters (reactive oxygen species levels, damage and defense) in fibroblasts of twelve well-characterized oxidative phosphorylation patients with a defect in the POLG1 gene, in the mitochondrial DNA-encoded tRNA-Leu gene (m.3243A>G or m.3302A>G) and in one of the mitochondrial DNA-encoded NADH dehydrogenase complex I (CI) subunits. All except two cell lines (one POLG1 and one tRNA-Leu) showed increased reactive oxygen species levels compared with controls, but only four (two CI and two tRNA-Leu) cell lines provided evidence for increased oxidative protein damage. The absence of a correlation between reactive oxygen species levels and oxidative protein damage implies differences in damage prevention or correction. This was investigated by gene expression studies, which showed adaptive and compensating changes involving antioxidants and the unfolded protein response, especially in the POLG1 group. This study indicated that patients display individual responses and that detailed analysis of fibroblasts enables the identification of patients that potentially benefit from antioxidant therapy. Furthermore, the fibroblast model can also be used to search for and test novel, more specific antioxidants or explore ways to stimulate compensatory mechanisms.
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Antioxidantes/uso terapêutico , Fibroblastos/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Fosforilação Oxidativa , Estresse Oxidativo , Adolescente , Adulto , Linhagem Celular , Criança , Pré-Escolar , DNA Polimerase gama , DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Feminino , Humanos , Lactente , Masculino , Doenças Mitocondriais/metabolismo , Mutação , RNA de Transferência de Leucina/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
CONTEXT: Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development. OBJECTIVE: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients. DESIGN AND METHODS: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index. INTERVENTION: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients. MAIN OUTCOME MEASUREMENTS: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training. RESULTS: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of ß-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training. CONCLUSIONS: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.
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Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias Musculares/fisiologia , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/terapia , Atividade Motora/fisiologia , Músculo Esquelético/metabolismo , Trifosfato de Adenosina/biossíntese , Idoso , Pressão Sanguínea/fisiologia , Composição Corporal/fisiologia , Índice de Massa Corporal , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/fisiologia , Diabetes Mellitus Tipo 2/terapia , Progressão da Doença , Feminino , Expressão Gênica/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Aptidão Física/fisiologia , Estado Pré-Diabético/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Barostat methodology is widely used for assessing visceral perception. Different barostat protocols are described with respect to the measurement of rectal compliance and visceral perception. The choice of protocols affects the duration, which is normally 60-90 min, and accuracy of the procedure. This study aimed to shorten the procedure by using the semi-random distension protocol for both compliance and visceral perception measurement and a correction based on rectal capacity (RC) instead of minimal distension pressure (MDP). METHODS: Twelve irritable bowel syndrome (IBS) patients (7 females) and 11 healthy controls (8 females) underwent a barostat procedure. Compliance was determined during both a staircase distension and a semi-random protocol. Visceral perception data were compared as a function of pressure or relative volume, corrected for MDP or RC, respectively. RESULTS: Compliance measurement using the semi-random protocol instead of the staircase distension protocol resulted in an overestimation in healthy volunteers, but not in IBS patients. The overall conclusion that IBS patients had a lower compliance compared to controls was not different between protocols. Data presentation of the visceral perception scores as a function of corrected volume instead of pressures corrected for MDP did not alter the conclusion that sensation scores in IBS patients were higher as compared to healthy controls. CONCLUSIONS: This study showed that barostat procedures may be shortened by approximately 20 min, without losing the ability to discriminate between healthy controls and IBS patients. A correction for RC instead of MDP may improve the accuracy of the procedure.
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Dilatação/métodos , Motilidade Gastrointestinal/fisiologia , Síndrome do Intestino Irritável/fisiopatologia , Reto/fisiopatologia , Adulto , Estudos de Casos e Controles , Protocolos Clínicos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Pressão , Fatores de TempoRESUMO
Defective complex I (CI) is the most common type of oxidative phosphorylation disease, with an incidence of 1 in 5000 live births. Here, whole genome expression profiling of fibroblasts from CI deficient patients was performed to gain insight into the cell pathological mechanism. Our results suggest that patient fibroblasts responded to oxidative stress by Nrf2-mediated induction of the glutathione antioxidant system and Gadd45-mediated activation of the DNA damage response pathway. Furthermore, the observed reduced expression of selenoproteins, might explain the disturbed calcium homeostasis previously described for the patient fibroblasts and might be linked to endoplasmic reticulum stress. These results suggest that both glutathione and selenium metabolism are potentially therapeutic targets in CI deficiency.
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Cálcio/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Redes e Vias Metabólicas/genética , Doenças Mitocondriais/genética , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Proteínas de Ciclo Celular/metabolismo , Pré-Escolar , Dano ao DNA , Estresse do Retículo Endoplasmático , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Glutationa/metabolismo , Homeostase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Selenoproteínas/metabolismoRESUMO
BACKGROUND: Visceral hypersensitivity is frequently observed in irritable bowel syndrome (IBS). Previous studies have shown that administration of a meal can aggravate symptoms or increase visceroperception in IBS patients. We investigated whether meal ingestion could increase the sensitivity of the barostat procedure for the detection of visceral hypersensitivity in IBS patients. METHODS: Seventy-one IBS patients and 30 healthy controls (HC) were included in the study. All subjects underwent a barostat procedure under fasted and postprandial conditions to measure visceroperception. Urge, discomfort, and pain were scored on a visual analog scale. Furthermore, percentages of hypersensitive IBS patients and HC were calculated and dynamic rectal compliance was assessed. KEY RESULTS: In IBS patients, urge, discomfort, and pain scores were significantly increased postprandially vs the fasted state. The HC showed increased scores for urge and pain only. Rectal dynamic compliance remained unaltered in both groups. Postprandial hypersensitivity percentages did not significantly differ vs the fasted state in IBS patients, nor in HC. CONCLUSIONS & INFERENCES: Postprandial barostat measurement enhances visceroperception in IBS but has no added value to detect visceral hypersensitivity in individual IBS patients.
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Ingestão de Alimentos , Síndrome do Intestino Irritável/fisiopatologia , Limiar da Dor/fisiologia , Dor Visceral/fisiopatologia , Adulto , Jejum , Feminino , Humanos , Masculino , Medição da Dor , Período Pós-Prandial , PressãoRESUMO
OBJECTIVE: Insulin resistance and type 2 diabetes mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. In this study, we identified the underlying molecular processes in preadipocytes of T2DM patients, a characteristic for the development of T2DM. DESIGN AND PARTICIPANTS: Preadipocyte cell cultures were prepared from subcutaneous fat biopsies of seven T2DM patients (age 53 ± 12 years; body mass index (BMI) 34 ± 5 kg m(-2)) and nine control subjects (age 51 ± 12 years; BMI 30 ± 3 kg m(-2)). Microarray analysis was used to identify altered processes between the T2DM and control preadipocytes. RESULTS: Gene expression profiling showed changed expression of transcription regulators involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were downregulated, and inflammation/apoptosis was upregulated in T2DM preadipocytes. CONCLUSION: Decreased expression of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage.
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Adipócitos/patologia , Adipogenia , Tecido Adiposo/patologia , Diferenciação Celular , Diabetes Mellitus Tipo 2/patologia , Perfilação da Expressão Gênica , Adipogenia/genética , Índice de Massa Corporal , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Transcrição GênicaRESUMO
Fermentation of dietary fibres by colonic microbes leads to the production of short chain fatty acids (mainly propionate, butyrate and acetate), which are utilized by the colonic mucosa. Previous studies showed positive effects of butyrate on parameters of oxidative stress, inflammation and apoptosis. Recent studies in rats, however, showed that butyrate increased visceral sensitivity. The aim of this study was to determine the effects of physiologically relevant concentrations of butyrate on visceral perception in healthy human subjects. Eleven healthy volunteers participated in this randomized double-blind, placebo controlled cross-over study. The study consisted of three periods of 1 week each, in which the volunteers daily self-administered rectal enemas containing 100, 50 mmol L(-1) butyrate, or placebo (saline) prior to sleeping. A rectal barostat measurement was performed at the start and the end of each test period for the measurement of pain, urge and discomfort. Butyrate treatment resulted in a dose-dependent reduction of pain, urge and discomfort throughout the entire pressure range of the protocol. At a pressure of 4 mmHg, 50 and 100 mmol L(-1) butyrate concentrations resulted in a 23.9% and 42.1% reduction of pain scores, respectively, and the discomfort scores decreased by 44.2% and 69.0% respectively. At a pressure of 67 mmHg, 50 and 100 mmol L(-1) of butyrate decreased the pain scores by 23.8% and 42%, respectively, and discomfort scores 1.9% and 5.2% respectively. Colonic administration of butyrate, at physiologically relevant concentrations, dose-dependently decreases visceral sensitivity in healthy volunteers.
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Butiratos/farmacologia , Enema , Motilidade Gastrointestinal/efeitos dos fármacos , Administração Retal , Butiratos/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Motilidade Gastrointestinal/fisiologia , Humanos , Masculino , Dor/prevenção & controle , Medição da Dor , Peristaltismo/efeitos dos fármacos , Peristaltismo/fisiologia , Reto/fisiopatologiaRESUMO
BACKGROUND: The m.3243A>G mutation in the mitochondrial tRNA(Leu(UUR)) gene is an example of a mutation causing a very heterogeneous phenotype. It is the most frequent cause (80%) of the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), but it can also lead in addition or separately to type 2 diabetes, deafness, renal tubulopathy and/or cardiomyopathy. METHODS: To identify pathogenic processes induced by this mutation, we compared global gene expression levels of muscle biopsies from affected and unaffected mutation carriers with controls. RESULTS AND CONCLUSIONS: Gene expression changes were relatively subtle. In the asymptomatic group 200 transcripts were upregulated and 12 were downregulated, whereas in the symptomatic group 15 transcripts were upregulated and 52 were downregulated. In the asymptomatic group, oxidative phosphorylation (OXPHOS) complex I and IV genes were induced. Protein turnover and apoptosis were elevated, most likely due to the formation of dysfunctional and reactive oxygen species (ROS) damaged proteins. These processes returned to normal in symptomatic patients. Components of the complement system were upregulated in both groups, but the strongest in the symptomatic group, which might indicate muscle regeneration--most likely, protein damage and OXPHOS dysfunction stimulate repair (protein regeneration) and metabolic adaptation (OXPHOS). In asymptomatic individuals these processes suffice to prevent the occurrence of symptoms. However, in affected individuals the repair process terminates, presumably because of excessive damage, and switches to muscle regeneration, as indicated by a stronger complement activation. This switch leaves increasingly damaged tissue in place and muscle pathology becomes manifest. Therefore, the expression of complement components might be a marker for the severity and progression of MELAS clinical course.
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Síndrome MELAS/genética , Mutação Puntual , RNA de Transferência de Leucina/genética , Adolescente , Adulto , Idoso , Apoptose , Criança , Pré-Escolar , Ativação do Complemento , Feminino , Perfilação da Expressão Gênica , Heterozigoto , Humanos , Síndrome MELAS/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Fosforilação Oxidativa , Proteínas/metabolismo , RNA de Transferência de Leucina/metabolismoRESUMO
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by left ventricular hypertrophy (LVH) predominantly affecting the interventricular septum. Cardiac myosin-binding protein C (cMyBP-C) mutations are common causes of FHC. Gene expression profiling was performed in left ventricles of 9-week-old wild-type mice, heterozygous cMyBP-C KO mice displaying asymmetric septal hypertrophy, and homozygous mice developing eccentric LVH. Knocking out one or two cMyBP-C genes leads primarily to gene expression changes indicating an increased energy demand, activation of the JNK and p38 parts of the MAPK pathway and deactivation of the ERK part, and induction of apoptosis. Altered gene expression for processes related to cardiac structure, contractile proteins, and protein turnover was also identified. Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice.
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Cardiomiopatia Hipertrófica Familiar/metabolismo , Proteínas de Transporte/metabolismo , Transtornos Cromossômicos/metabolismo , Regulação da Expressão Gênica , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Animais , Apoptose/genética , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/patologia , Proteínas de Transporte/genética , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , MAP Quinases Reguladas por Sinal Extracelular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Heterozigoto , Homozigoto , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Miocárdio/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Septo Interventricular/metabolismo , Septo Interventricular/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Heritability estimates of birth weight have been inconsistent. Possible explanations are heritability changes during gestational age or the influence of covariates (e.g. chorionicity). The aim of this study was to model birth weights of twins across gestational age and to quantify the genetic and environmental components. We intended to reduce the common environmental variance to increase heritability and thereby the chance of identifying candidate genes influencing the genetic variance of birth weight. Perinatal data were obtained from 4232 live-born twin pairs from the East Flanders Prospective Twin Survey, Belgium. Heritability of birth weights across gestational ages was estimated using a non-linear multivariate Gaussian regression with covariates in the means model and in covariance structure. Maternal, twin-specific, and placental factors were considered as covariates. Heritability of birth weight decreased during gestation from 25 to 42 weeks. However, adjusting for covariates increased the heritability over this time period, with the highest heritability for first-born twins of multipara with separate placentas, who were staying alive (from 52% at 25 weeks to 30% at 42 weeks). Twin-specific factors revealed latent genetic components, whereas placental factors explained common and unique environmental factors. The number of placentas and site of the insertion of the umbilical cord masked the effect of chorionicity. Modeling genetic and environmental factors leads to a better estimate of their role in growth during gestation. For birth weight, mainly environmental factors were explained, resulting in an increase of the heritability and thereby the chance of finding genes influencing birth weight in linkage and association studies.
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Peso ao Nascer/genética , Meio Ambiente , Feminino , Desenvolvimento Fetal/genética , Idade Gestacional , Inquéritos Epidemiológicos , Humanos , Recém-Nascido , Modelos Genéticos , Seleção de Pacientes , Gravidez , Gêmeos DizigóticosRESUMO
To extract functional information on genes and processes from large expression datasets, analysis methods are required that can computationally deal with these amounts of data, are tunable to specific research questions, and construct classifiers that are not overspecific to the dataset at hand. To satisfy these requirements, a stepwise procedure that combines elements from principal component analysis and discriminant analysis, was developed to specifically retrieve genes involved in processes of interest and classify samples based upon those genes. In a global expression dataset of 300 gene knock-outs in Saccharomyces cerevisiae, the procedure successfully classified samples with similar 'cellular component' Gene Ontology annotations of the knock-out gene by expression signatures of limited numbers of genes. The genes discriminating 'mitochondrion' from the other subgroups were evaluated in more detail. The thiamine pathway turned out to be one of the processes involved and was successfully evaluated in a logistic model to predict whether yeast knock-outs were mitochondrial or not. Further, this pathway is biologically related to the mitochondrial system. Hence, this strongly indicates that our approach is effective and efficient in extracting meaningful information from large microarray experiments and assigning functions to yet uncharacterized genes.
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Biologia Computacional/métodos , Perfilação da Expressão Gênica , Genes Mitocondriais/genética , Genoma Fúngico/genética , Mutação/genética , Saccharomyces cerevisiae/genética , Tiamina/biossíntese , Regulação Fúngica da Expressão Gênica , Genes Fúngicos/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Cardiac hypertrophy is an important risk factor for cardiac morbidity and mortality. To unravel the underlying pathogenic genetic pathways, we hybridized left ventricular RNA from Transverse Aortic Constriction mice at 48 h, 1 week, and 2, 3, and 8 weeks after surgery to microarrays containing a 15K fetal cDNA collection. Key processes involved an early restriction in the expression of metabolic genes, accompanied by increased expression of genes related to growth and reactivation of fetal genes. Most of these genes returned to basal expression levels during the later, compensated hypertrophic phase. Our findings suggest that compensated hypertrophy in these mice is established by rapid adaptation of the heart at the cost of gene expression associated with metabolic activity, with only temporary expression of possible maladaptive processes. Therefore, the transient early changes may reflect a beneficial response to pressure overload, as deterioration of cardiac hemodynamic function or heart failure does not occur.