RESUMO
Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.
Assuntos
Linfócitos B/citologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Diferenciação Celular/fisiologia , Células Precursoras de Linfócitos B/citologia , Transativadores/metabolismo , Animais , Linfócitos B/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem da Célula , Separação Celular , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Regulação da Expressão Gênica/fisiologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Linfopoese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Células Precursoras de Linfócitos B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genéticaAssuntos
Doenças Genéticas Inatas/genética , Janus Quinase 2/genética , Mutação de Sentido Incorreto , Policitemia Vera/genética , Trombocitose/genética , Adulto , Substituição de Aminoácidos , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/patologia , Humanos , Policitemia Vera/sangue , Policitemia Vera/etiologia , Policitemia Vera/patologia , Trombocitose/sangue , Trombocitose/complicações , Trombocitose/patologiaRESUMO
INTRODUCTION AND IMPORTANCE: A case of Low-grade endometrial stromal sarcoma (LG-ESS) invading the great vessels is rare. CASE PRESENTATION: A 34-year-old female who had no past history presented to a previous hospital with abdominal distension. Magnetic resonance imaging revealed a 15 cm pelvic mass beside the uterus, and only the pelvic mass was removed at the surgery. The tumor was judged to be a LG-ESS. The patient chose to be observed to preserve her fertility, and no adjuvant treatment was undertaken. Two years later, she was referred to our hospital due to recurrence of the pelvic mass. Enhanced computed tomography revealed a large tumor in the vena cava which extended from the left internal iliac vein and which originated from the pelvic tumor. An operation was performed by a multidisciplinary team. Complete resection of the tumor was achieved with a radical hysterectomy, bilateral salpingo-oophorectomy, removal of recurrent pelvic masses and the intravascular tumor. We diagnosed a recurrence of LG-ESS. She received a postoperative adjuvant therapy of LG-ESS. CLINICAL DISCUSSION: Patients with fertility-sparing treatment had higher recurrence rates. In cases of tumor intravenous extension, we should make every effort to extract the tumor to avoid sudden death. CONCLUSION: This case highlights the importance of a multidisciplinary approach in treating this rare tumor with intravascular extension. In particular, patients with LG-ESS who receive fertility-sparing surgery should undertake postoperative chemotherapy or radiotherapy in order to reduce the risk of recurrence, as was in this case.
RESUMO
OBJECTIVES: Heme oxygenase 1 (HO-1) is rapidly induced by stress, degrading pro-oxidant heme into carbon monoxide, bilirubin, and free iron (Fe). Induction of HO-1 is an important defense mechanism against tissue injury. Here, we tested the hypothesis that HO-1 is activated in the myocardium after acute myocardial infarction (AMI) in humans. METHODS: Changes in the HO-1 activity after AMI were analyzed by measuring serum levels of bilirubin and Fe. Blood samples were collected in patients with AMI (n = 41) serially after the interventional therapy and compared with non-AMI subjects (n = 18). HO-1 protein levels were measured in a sample of AMI patients (n = 12). RESULTS: In AMI patients, but not in non-AMI subjects, serum levels of bilirubin (1.57 fold, P < 0.001) and Fe (1.35 fold, P < 0.01) were transiently elevated, both levels peaking 18-21 hours after the start of sampling. The peak changes in the levels of bilirubin and Fe in AMI patients were significantly correlated with each other. Furthermore, the serum HO-1 protein level was elevated, and its change was significantly correlated with the change in bilirubin level (r = 0.82, P < 0.005). Those with a high bilirubin response (peak levels >0.5 mg/dL) had richer collateral flow into the ischemic myocardium. CONCLUSIONS: These results suggest that heme oxygenase (HO) was activated following AMI, and it was detectable in the serum. Our data provide the first evidence of HO-1 induction following stress in humans. The change in bilirubin level may be a novel index for high collateral flow formation following AMI.
Assuntos
Bilirrubina/sangue , Heme Oxigenase-1/sangue , Infarto do Miocárdio/sangue , Idoso , Estudos de Casos e Controles , Circulação Colateral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Ferro/sangue , Masculino , Miocárdio/metabolismoRESUMO
AIM: To clarify the correlation between malnutrition, muscle mass and oral status, and swallowing function recovery in stroke patients receiving enteral nutrition. METHODS: Patients with stroke and dysphagia receiving any amount of enteral nutrition in rehabilitation wards from 2012 to 2016 were eligible for inclusion in this retrospective study. On admission, body composition by bioimpedance analysis, malnutrition confirmed by the European Society for Clinical Nutrition and Metabolism criteria, oral status, functional independence measure and demographic data were collected. Characteristics were compared between "oral intake alone" and "artificial nutrition" groups based on the discharge status. Kaplan-Meier methods and the Cox proportional hazards model were used to determine explanatory factors for the probability of full oral intake. RESULTS: Among 174 patients, 113 were analysed (55 women; median age, 77 years). Overall, 61% and 39% were classified as "oral intake alone" and "artificial nutrition," respectively. Days from onset to admission to rehabilitation wards and motor Functional Independence Measure were higher in the "oral intake alone" group. Kaplan-Meier analysis demonstrated that patients with lower muscle mass exhibited lower probability of full oral intake (P = .009). The Cox proportional hazards model suggested that lower muscle mass (hazard ratio, 0.493; 95% CI, 0.286-0.850) and poor oral hygiene (hazard ratio, 0.573; 95% CI, 0.333-0.987) were independently correlated with "oral intake alone" status. Malnutrition and other oral status are not related to achieving full oral intake. CONCLUSIONS: Skeletal muscle mass and oral hygiene are independently correlated with full oral intake among stroke patients receiving enteral nutrition during the rehabilitation phase.
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Nutrição Enteral , Acidente Vascular Cerebral , Idoso , Humanos , Músculos , Estado Nutricional , Estudos RetrospectivosRESUMO
BACKGROUND: Although the evaluation of fluid status in hemodialysis (HD) patients is useful, relationship among pulmonary capillary wedge pressure (PCWP), dry body weight (DW) and natriuretic peptide has not been elucidated. In addition, there has been no objective marker for instantaneously monitoring hemodynamic improvement in response to HD. We previously reported that PCWP and time constant of left ventricular pressure decline (Tau) can be noninvasively estimated (ePCWP and eTau) by speckle tracking echocardiography (STE). The aim of this study was to elucidate the relationship among ePCWP, eTau, DW and natriuretic peptide in patients undergoing HD. METHODS: We measured ePCWP and body weight (BW) by STE in 81 patients and ANP and BNP by blood examination in 31 patients just before and after HD during sinus rhythm. RESULTS: The ePCWP decreased after HD, and this was associated with reductions in ln ANP, eTau and BW (r = 0.523, 0.271 and 0.814, respectively, p < 0.05). The % change in ePCWP was not correlated with the % change in ln BNP (p = 0.47). The change in ePCWP had a stronger correlation with the % change in BW than the change in any other parameters. CONCLUSIONS: The ePCWP is more sensitive to estimate the change in BW during HD than any other parameters such as ANP and BNP. These results indicated that a substantial amount of excess fluid can be assessed real-time by STE using ePCWP.
Assuntos
Ecocardiografia Tridimensional/métodos , Hemodinâmica , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/terapia , Diálise Renal , Idoso , Biomarcadores/sangue , Peso Corporal , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Peptídeos Natriuréticos/sangue , Pressão Propulsora PulmonarRESUMO
A 55-year-old woman underwent total hysterectomy. She suffered from tuberous sclerosis and was complicated with lymphangioleiomyomatosis and renal angiomyolipoma. There have been only a few reports of anesthetic management on patients with these three diseases. Anesthesia was maintained with combined spinal-epidural anesthesia. Patients with tuberous sclerosis should be examined precisely. This case was managed carefully to avoid pneumothorax and acute bleeding from renal angiomyolipoma. There was no postoperative anesthesia-related complications.
Assuntos
Anestesia Epidural , Raquianestesia , Angiomiolipoma/complicações , Histerectomia , Neoplasias Renais/complicações , Linfangioleiomiomatose/complicações , Esclerose Tuberosa/complicações , Doença Aguda , Perda Sanguínea Cirúrgica/prevenção & controle , Feminino , Humanos , Complicações Intraoperatórias/prevenção & controle , Pessoa de Meia-Idade , Pneumotórax/prevenção & controleRESUMO
BACKGROUND: Recently, attention has been focused on the cardiovascular protective effects of beet juice (BJ) with high amounts of nitrate. In this study, we examined the effect of BJ supplementation in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). METHODS: MCT (60 mg/kg) was subcutaneously administered to rats, and BJ (prepared by dissolving BJ powder at a concentration of 1 g/l or 10 g/l in drinking water) supplementation was started from the day of, 1 week before, and 2 weeks after MCT injection. Saline-injected rats given drinking water were used as controls. RESULTS: Low-dose BJ supplementation starting from the day of MCT injection exerted protective effects on the MCT-induced elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arterial remodeling, without causing a significant increase in plasma nitrite plus nitrate (NOx) levels. On the other hand, such beneficial effects were not observed with high-dose BJ supplementation, although the NOx levels were slightly higher than those in the low-dose group. In addition, low-dose BJ supplementation starting from 1 week before MCT injection did not improve PH symptoms, as described above. Furthermore, low-dose BJ supplementation starting from 2 weeks after MCT injection was ineffective against functional and morphological alterations in pulmonary circulation associated with MCT-induced PH. CONCLUSIONS: Habitual ingestion of a suitable amount of BJ could be a potential option for preventing PH. However, beneficial effects cannot be expected when PH has developed to some degree.
Assuntos
Pressão Arterial , Beta vulgaris , Suplementos Nutricionais , Sucos de Frutas e Vegetais , Hipertensão Arterial Pulmonar/prevenção & controle , Artéria Pulmonar/fisiopatologia , Animais , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Masculino , Monocrotalina , Óxido Nítrico/metabolismo , Raízes de Plantas , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Remodelação Vascular , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular DireitaRESUMO
We report the case of a 30-year-old woman who complained of a painful palpable mass. Magnetic resonance imaging revealed an ill-defined mass approximately 8 cm in diameter with internal microcytic components. The mass diffusely involved the subcutaneous tissues, the muscles of the pelvic wall, and urinary bladder via a postoperative scar and resembled endometriosis. The histopathologic diagnosis was mucinous adenocarcinoma arisen from the urachal remnant. This is a very rare case of urachal adenocarcinoma arising mainly in the pelvic wall and mimicking endometriosis on MRI.
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AIMS: In this study, we examined whether a disruption in the balance between nitric oxide (NO)-sensitive and -insensitive soluble guanylate cyclase (sGC) is observed in pulmonary hypertension (PH) and whether treatment with NO-enhancing drugs can halt disease progression. MAIN METHODS: Rats were injected subcutaneously with saline or 60â¯mg/kg monocrotaline (MCT). At 14â¯days after injection, the vascular reactivity of isolated extralobar pulmonary arteries was assessed by organ chamber technique. In a separate experiment, isosorbide mononitrate (0.3 or 1â¯g/L) or sodium nitrite (30 or 300â¯mg/L) was administered in drinking water for the last 14â¯days (from day 15 to day 28), and their therapeutic potential was evaluated. KEY FINDINGS: The NO-sensitive sGC stimulant BAY 41-2272 and the NO-insensitive sGC stimulant BAY 60-2770 both relaxed the pulmonary arteries, which was comparable between saline- and MCT-injected rats. Treatment with isosorbide mononitrate suppressed the MCT-induced right ventricular systolic pressure (RVSP) elevation and pulmonary arterial medial thickening but not right ventricular hypertrophy. However, the beneficial effects on RVSP and pulmonary vascular remodeling were not observed when a high dose was administered. The same results were obtained following the sodium nitrite treatment. Interestingly, NO-enhancing drugs did not increase plasma nitrite plus nitrate levels at a dose that provided the greatest therapeutic advantage. SIGNIFICANCE: These findings suggest that the balance between NO-sensitive and -insensitive sGC is not disrupted in the early stage of MCT-induced PH. Furthermore, supplementation with an adequate amount of NO may be a useful therapy to prevent the progression of PH.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/farmacologia , Hipertensão Pulmonar/enzimologia , Monocrotalina/toxicidade , Óxido Nítrico/farmacologia , Artéria Pulmonar/enzimologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Masculino , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: The goal of the present study was to determine whether seropositivity to Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV) is associated with systemic inflammation and endothelial dysfunction in healthy male subjects. BACKGROUND: Chronic infection with certain bacteria and viruses may play an important role in inflammation as the pathogenesis of atherosclerosis. METHODS: The serum levels of immunoglobulin G antibodies to HP, CP, CMV, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were determined in 81 healthy Japanese men (40 +/- 10 years of age). High-frequency ultrasonographic imaging of the brachial artery was used to study endothelium-dependent (flow-mediated vasodilation) and endothelium-independent (nitroglycerin-induced) vasodilation. RESULTS: Prevalences of seropositive antibodies to HP, CP, and CMV were 67.9%, 61.7%, and 56.8%, respectively. Infection with HP, CP, or CMV had no relationship with age, blood pressure, or level of serum glucose, lipid, or soluble vascular cell adhesion molecule-1. The levels of C-reactive protein and soluble intercellular adhesion molecule-1 were significantly higher, and flow-mediated vasodilation was significantly lower in subjects with seropositive antibodies to HP than in subjects with seronegative antibodies to HP. Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Chronic infection with HP may be involved in the development of the atherosclerosis via endothelial dysfunction and systemic and vascular inflammation.
Assuntos
Endotélio Vascular/fisiopatologia , Infecções por Helicobacter/complicações , Helicobacter pylori , Inflamação/etiologia , Adulto , Anticorpos Antibacterianos/sangue , Anticorpos Antivirais/sangue , Arteriosclerose/etiologia , Proteína C-Reativa/análise , Chlamydophila pneumoniae/imunologia , Citomegalovirus/imunologia , Infecções por Helicobacter/sangue , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/imunologia , Humanos , Imunoglobulina G/sangue , Molécula 1 de Adesão Intercelular/sangue , Masculino , Estudos Soroepidemiológicos , Molécula 1 de Adesão de Célula Vascular/sangue , Vasodilatação/fisiologiaRESUMO
Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca2+ channels were detected in the vascular endothelium. The purpose of the present study was to clarify the role of T-type Ca2+ channels in endothelial function. We studied flow-mediated vasodilation (FMD) and sublingual nitroglycerin (NTG)-induced vasodilation in the brachial artery. Forty patients with essential hypertension were randomly assigned to treatment with efonidipine, a T- and L-type Ca2+ channel blocker, or with nifedipine, an L-type Ca2+ channel blocker. Twenty healthy normotensive individuals were included as a control group. In patients with essential hypertension, FMD was attenuated and NTG was similar that of compared to healthy controls. After 12 weeks, the decrease in mean blood pressure in the efonidipine and nifedipine groups were similar. The endothelial function index, a ratio of FMD/NTG, was significantly increased by efonidipine (73 +/- 24 to 94 +/- 20%) but unchanged by nifedipine. Urinary excretion 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (LDL) were decreased by efonidipine but unchanged by nifedipine. These results suggest that a T-type Ca2+ channel blocker, but not an L-type Ca2+ channel blocker, may improve vascular endothelial dysfunction in patients with essential hypertension via a reduction in oxidative stress.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Vasodilatação/efeitos dos fármacos , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Artéria Braquial/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Casos e Controles , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/uso terapêutico , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêuticoRESUMO
Abnormal Ca2+ handling and enhanced aggregation response have been reported in platelets from spontaneously hypertensive rats (SHR) and patients with essential hypertension, and thought to be involved in the progression of target organ damage of hypertension. It is important to examine whether antihypertensive therapy can improve the abnormal platelet response in hypertension. We investigated the effect of antihypertensive treatment such as amlodipine and cilazapril on Ca2+ handling and aggregation response in SHR platelets. Four-week-old male SHR were divided into three groups. Each group was treated with amiodipine (A: 10 mg/kg/day), cilazapril (C: 10 mg/kg/day) or vehicle (V) for 8 weeks by gavage. At 12-week-old, platelet [Ca2+]i was measured with fura-2 in each group of SHR and age-matched Wistar-Kyoto rats (WKY) as normal control. Systolic blood pressure in amlodipine and cilazapril treated groups were similar with WKY and significantly lower than vehicle treated group (A: 124 +/- 9, C: 126 +/- 9, WKY: 122 +/- 10 and V: 180 +/- 9 mmHg, respectively). The basal [Ca2+]i in the three groups of SHR were similar and higher than WKY (A: 47 +/- 1.7, C: 47 +/- 1.2, V: 48 +/- 3.9 and WKY: 40 +/- 4.0 nmol/l, respectively). There were no significant differences in thrombin (0.1 U/ml)-stimulated [Ca2+]i rise in the presence or absence of extracellular Ca2+ among the three groups of SHR and these were higher than WKY. Intracellular Ca2+ discharge capacity, assessed by the ionomycinstimulation was similar in the all groups. Thrombin-induced maximum platelet aggregation responses in the three groups of SHR were similar and higher than WKY. The antihypertensive treatment of Ca2+ antagonist or ACE inhibitor gave no change in intraplatelet Ca2+ metabolism in SHR. These results support the hypothesis that an abnormal Ca2+ handling in SHR platelet is genetically determined and not improved by hypotensive therapy.
Assuntos
Anlodipino/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Plaquetas/metabolismo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cálcio/sangue , Cilazapril/uso terapêutico , Hipertensão/tratamento farmacológico , Animais , Plaquetas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peso Corporal/efeitos dos fármacos , Citosol/efeitos dos fármacos , Citosol/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/sangue , Hipertensão/genética , Ionomicina , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Trombina/farmacologiaRESUMO
We have established a clinical routine method for evaluating the endothelial function in forearm circulation in humans. Flow-mediated vasodilation(FMD) was used as the endothelium-dependent and the response to nitroglycerin(NTG) as the endothelium-independent vasodilation. Diameter of the brachial artery was measured by high-frequency ultrasonographic imaging before and after hyperemia following artery occlusion. Because vasodilation reached the maximal level when the artery was occluded for 5 min, this time was selected as the occlusion time. FMD was greater (12 vs 9%) after upper-arm occlusion than after forearm occlusion. The peak time to maximal vasodilation was 50 sec after forearm occlusion and 70 sec after upper-arm occlusion. During NO synthesis inhibitor infusion, vasodilation after forearm occlusion was abolished, whereas that after upper-arm occlusion was attenuated by half. Therefore, the mechanisms for FMD may differ by occlusion position. The response to NTG was attenuated by aging. FMD was significantly decreased by coronary artery disease and coronary risk factors such as hypertension, hyperlipidemia and diabetes, but the response to NTG was not changed by these diseases. These measurements may offer useful tools for assessment of endothelial function.
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Arteriosclerose/diagnóstico , Artéria Braquial , Técnicas de Diagnóstico Cardiovascular , Endotélio Vascular/fisiopatologia , Vasodilatação/fisiologia , Arteriosclerose/etiologia , Fenômenos Biomecânicos , Doença das Coronárias/fisiopatologia , Diabetes Mellitus/fisiopatologia , Humanos , Hiperlipidemias/fisiopatologia , Hipertensão/fisiopatologia , Nitroglicerina , Fatores de RiscoRESUMO
Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1(-/-)) mice. TAC for 3 weeks in wild-type control (Bach1(+/+)) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and betaMHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and betaMHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1(-/-) mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Heme Oxigenase-1/genética , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Pressão Sanguínea , Peso Corporal , Ecocardiografia , Regulação Enzimológica da Expressão Gênica/fisiologia , Frequência Cardíaca , Heme Oxigenase-1/metabolismo , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Estresse Oxidativo/fisiologia , Transcrição Gênica/fisiologia , Regulação para Cima/fisiologia , Remodelação Ventricular/fisiologiaRESUMO
Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1(-/-)) and wild-type (Bach1(+/+)) mice. In Bach1(-/-) mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1(+/+) mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice. Pretreatment of Bach1(-/-) mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão/genética , Animais , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/genética , Ventrículos do Coração/metabolismo , Heme Oxigenase-1/metabolismo , Imuno-Histoquímica , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Isquemia Miocárdica/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controleRESUMO
The neural-inducing activity of artificially mesodermalized ectoderm was examined. The competent ectoderm of earlyCynops gastrula was mesodermalized by being placed in contact withCarassius swimbladder. The mesodermalized ectoderm was combined with ectoderm isolated from various developmental stages of a gastrula. Neural differentiation were observed in half the combinants, even in 18 h ectoderm, which is considered to have lost its neural competence within 6 h. This indicates that mesodermalized ectoderm is capable of inducing neural tissues at the very time it comes into contact with 18 h ectoderm. From the present study, the neural-inducing activity of mesodermalized cells may possibly be closely connected to the early process of their mesodermalization.
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Kinins have been shown to play a cardioprotective role during myocardial ischemia. However, the localization of each of the components of the kallikrein-kinin system in the heart has not been determined in a cell type-specific manner. Recently, mK1 has been identified as the major tissue kallikrein with the strongest bradykinin-forming activity among the products of the mouse tissue kallikrein gene superfamily. In the study presented here, we investigated the localizations of mK1, kininogen and bradykinin B2 receptors (B2Rs) in ischemic and non-ischemic left ventricles by immunohistochemistry. Kininogen, which contains bradykinin as a surface epitope, was detected by an anti-bradykinin antibody. Changes in the amounts of mK1 and B2R were evaluated by Western blot analysis. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery for 60 min followed by reperfusion for 24 h. mK1 and B2Rs were most abundantly expressed in the vascular endothelium and, to a lesser extent, in fibroblasts. No immunohistochemical signal of these molecules was detected in myocytes. Kininogen was localized in the vascular endothelium and the smooth muscle layer. Myocardial ischemia, although it had no effect on the localization of these molecules, increased the amounts of mK1 and B2R. We have obtained immunohistochemical evidence that all components of the tissue kallikrein-kinin system are present in the mouse heart. The coronary artery is the major site of kallikrein-kinin activity both in ischemic and non-ischemic hearts.
Assuntos
Sistema Calicreína-Cinina/imunologia , Isquemia Miocárdica/enzimologia , Calicreínas Teciduais/metabolismo , Animais , Western Blotting , Bradicinina/biossíntese , Bradicinina/imunologia , Bradicinina/farmacocinética , Vasos Coronários/enzimologia , Endotélio Vascular/enzimologia , Epitopos/imunologia , Epitopos/metabolismo , Ventrículos do Coração/enzimologia , Ventrículos do Coração/imunologia , Ventrículos do Coração/ultraestrutura , Técnicas Imunoenzimáticas , Cininogênio de Alto Peso Molecular/imunologia , Cininogênio de Alto Peso Molecular/metabolismo , Cininogênio de Baixo Peso Molecular/imunologia , Cininogênio de Baixo Peso Molecular/metabolismo , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/fisiopatologia , Receptor B2 da Bradicinina/efeitos dos fármacos , Receptor B2 da Bradicinina/imunologia , Receptor B2 da Bradicinina/ultraestrutura , Reperfusão , Fatores de Tempo , Calicreínas Teciduais/biossíntese , Calicreínas Teciduais/genéticaRESUMO
The aim of this study was to determine the role of the AT2 receptor (AT2R) in left ventricular (LV) remodeling after myocardial infarction (MI). The left anterior descending arteries were ligated in AT2R gene knockout (Agtr2-) and wild-type (Agtr2+) mice. The LV remodeling was evaluated by echocardiography and histology over a period of 2 weeks after MI. The infarct sizes in hearts excised from Agtr2+ and Agtr2- mice on day 1 were similar. The mortality rate of Agtr2- mice (62.9%) on day 14 after MI was significantly (P<0.05) higher than that of Agtr2+ mice (39.7%). Accordingly, LV/body weight ratios (3.7+/-0.2 versus 3.0+/-0.1 on day 14) and LV end-diastolic (4.8+/-0.3 versus 3.9+/-0.4 mm on day 7) and end-systolic (4.4+/-0.3 versus 3.2+/-0.6 mm on day 7) dimensions evaluated by echocardiography were significantly greater in Agtr2- than in Agtr2+ mice. The rates of ventricular arrhythmia, rates of cardiac rupture, and blood pressures in the 2 strains were similar after MI. Myocyte cross-sectional areas were increased after MI, but the magnitudes were similar in Agtr2+ and Agtr2- mice, indicating the greater increases in LV dimensions and weight in Agtr2- mice are due to elongation of myocyte length and/or an increase in the interstitial weight (including vasculatures, infiltrated cells, and interstitial fluid). Interstitial fibrosis in remote myocardium was not evident in either strain. These results indicate AT2R plays a significant role in the protection against early development of LV dilation, thereby reducing the early mortality rate after MI.