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1.
Hypertens Res ; 46(3): 667-678, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36376492

RESUMO

Previously, we showed that augmented O-linked N-acetylglucosaminylation (O-GlcNAcylation) mitigates cardiac remodeling in O-GlcNAc transferase-transgenic (Ogt-Tg) mice exposed to acute (2-week) intermittent hypoxia (IH) by suppressing nuclear factor of activated T cells (NFAT) and nuclear factor kappa B (NF-κB) via the O-GlcNAcylation of glycogen synthase kinase 3 beta (GSK-3ß) and NF-κB p65. Because this effect is time dependent, we exposed Ogt-Tg mice to IH for 4 weeks (IH4W) in the present study. O-GlcNAcylation was significantly enhanced in Ogt-Tg mice vs. wild-type (WT) mice exposed to normoxia and IH4W. Total O-GlcNAcylation levels were significantly increased in WT and Ogt-Tg mice after IH4W vs. normoxia. After IH4W, Ogt-Tg mice displayed significantly exacerbated signs of cardiac hypertrophy and fibrosis in the right ventricles (RVs) but not the left ventricles (LVs). Echocardiography revealed IH4W-induced right ventricular dysfunction. Phosphorylated GSK-3ß levels were increased in Ogt-Tg mice vs. WT mice after IH4W, whereas phosphorylated NF-κB p65 levels were unaffected. Mitophagy, which is associated with cardiac dysfunction, was increased in the RVs of Ogt-Tg mice after IH4W. Furthermore, the levels of phosphorylated dynamin-related protein 1 (p-Drp1) were significantly increased, and the expression of mitofusin-2 (MFN2) was significantly decreased. In human embryonic kidney cells, mitochondrial uncoupler-induced mitochondrial dysfunction was accelerated in Ogt-overexpressing cells. In addition to increasing the levels of phosphorylated Smad2, IH4W promoted cardiac fibrosis in the RVs of Ogt-Tg mice. Thus, augmented O-GlcNAcylation may aggravate IH4W-induced right ventricular dysfunction and remodeling by promoting hypertrophy, mitophagy, and fibrosis via GSK-3ß inactivation, an increased p-Drp-1/MFN2 ratio, and Smad2 activation, respectively.


Assuntos
NF-kappa B , Disfunção Ventricular Direita , Camundongos , Humanos , Animais , NF-kappa B/metabolismo , Glicogênio Sintase Quinase 3 beta , Mitofagia , Camundongos Transgênicos , Hipóxia , Cardiomegalia , Fibrose
2.
ESC Heart Fail ; 8(5): 3885-3893, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34327841

RESUMO

AIMS: Oxidative stress plays an important role in the development and progression of heart failure (HF). Although exercise and oxidative stress are closely related, the effect of acute exercise on reactive oxygen species production and the fluctuation on prognosis are unclear. METHODS AND RESULTS: We enrolled 94 patients who were hospitalized for worsening HF (mean age 68.0 ± 14.5 years old, 63.8% male). The changes in diacron-reactive oxygen metabolites (d-ROM) values, a marker of oxidative stress, before and after a cardiopulmonary exercise test were considered as Δd-ROM. The mean follow-up period was 24 ± 13 months, during which 15 patients had all-cause death or left ventricular assist system implantation. Kaplan-Meier analysis demonstrated that all-cause death or left ventricular assist system implantation was significantly higher in the Δd-ROM-positive group than in the Δd-ROM-negative group (log-rank P = 0.047). Elevated Δd-ROM levels were associated with increased mortality risk. Multivariate analysis adjusted for body mass index and peak oxygen uptake revealed that Δd-ROM was an independent prognostic factor of adverse events (Tertile 3 vs. 1; hazard ratio: 4.57; 95% confidence interval: 1.21-29.77; P = 0.022). CONCLUSIONS: Patients with HF who underwent a cardiopulmonary exercise test and had an increased oxidative stress marker level had a poor prognosis. The appropriate exercise intensity could be determined by evaluating the changes in oxidative stress status in response to acute exercise in patients with HF.


Assuntos
Insuficiência Cardíaca , Idoso , Idoso de 80 Anos ou mais , Exercício Físico , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Prognóstico
3.
Biol Pharm Bull ; 44(5): 669-677, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33612567

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Rivaroxabana/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Hipóxia , Indóis , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , NF-kappa B/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Pirróis , Ratos Sprague-Dawley , Rivaroxabana/farmacologia
4.
Hypertens Res ; 42(12): 1858-1871, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409917

RESUMO

Type 2 diabetes mellitus (T2DM) has been reported to be associated with cardiac remodeling. Although O-GlcNAcylation is known to be elevated in diabetic and ischemic hearts, the effects of O-GlcNAcylation on cardiac remodeling induced by intermittent hypoxia (IH), such as sleep apnea syndrome (SAS), remain unknown. To evaluate the effects, we induced IH in wild-type (WT) and transgenic O-GlcNAc transferase (Ogt-Tg) mice. Two weeks of IH increased O-GlcNAcylation in the heart tissues of both strains of mice, whereas O-GlcNAcylation in Ogt-Tg mice was significantly higher than that in WT mice under both normoxic and IH conditions. WT mice exhibited cardiac remodeling after IH, whereas cardiac remodeling was significantly attenuated in Ogt-Tg mice. Oxidative stress and apoptosis increased after IH in both strains of mice, whereas the rate of increase in these processes in Ogt-Tg mice was significantly lower than that in WT mice. To examine the mechanism of cardiac remodeling attenuation in Ogt-Tg mice after IH, the effects of O-GlcNAcylation on the activities of the master regulators nuclear factor of activated T cells (NFAT) and NF-κB were determined. The O-GlcNAcylation of GSK-3ß, a negative regulator of NFAT, was significantly increased in Ogt-Tg mice, whereas the phosphorylation of GSK-3ß was reciprocally reduced. The same result was observed for NF-κB p65. An in vitro reporter assay showed that the augmentation of O-GlcNAcylation by an O-GlcNAcase inhibitor suppressed NFAT and NF-κB promoter activity. These data suggest that augmented O-GlcNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-κB activities through the O-GlcNAcylation of GSK-3ß and NF-κB p65.


Assuntos
Hipóxia/patologia , N-Acetilglucosaminiltransferases/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Remodelação Ventricular , Acilação , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Ecocardiografia , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , N-Acetilglucosaminiltransferases/genética , Estresse Oxidativo , Fosforilação
5.
J Pharmacol Sci ; 139(2): 112-119, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638989

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg-1·day-1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-ß1 (TGF-ß1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-ß1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Fibrose , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Ratos Endogâmicos F344 , Ratos Wistar , Fator de Crescimento Transformador beta1/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
6.
J Pharmacol Sci ; 137(3): 274-282, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30055890

RESUMO

Patients with obstructive sleep apnea (OSA) have a high prevalence of atrial fibrillation (AF). Rivaroxaban, a coagulation factor Xa inhibitor, has recently been reported to show pleiotropic effects. This study investigated the influence of rivaroxaban on cardiac remodeling caused by intermittent hypoxia (IH). Male C57BL/6J mice were exposed to IH (repeated cycles of 5% oxygen for 1.5 min followed by 21% oxygen for 5 min) for 28 days with/without rivaroxaban (12 mg/kg/day) or FSLLRY, a protease-activated receptor (PAR)-2 antagonist (10 µg/kg/day). IH caused endothelial cell degeneration in the small arteries of the right atrial myocardium and increased the level of %fibrosis and 4-hydroxy-2-nonenal protein adducts in the left ventricular myocardium. IH also increased the expression of PAR-2 as well as the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and nuclear factor-kappa B (NF-κB) were increased in human cardiac microvascular endothelial cells. However, rivaroxaban and FSLLRY significantly suppressed these changes. These findings demonstrate that rivaroxaban attenuates both atrial and ventricular remodeling induced by IH through the prevention of oxidative stress and fibrosis by suppressing the activation of ERK and NF-κB pathways via PAR-2. Treatment with rivaroxaban could potentially become a novel therapeutic strategy for cardiac remodeling in patients with OSA and AF.


Assuntos
Inibidores do Fator Xa/farmacologia , Hipóxia/complicações , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/patologia , Células Cultivadas , Células Endoteliais/patologia , Fibrose/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Miocárdio/patologia , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/metabolismo , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia
7.
Heart Vessels ; 33(11): 1325-1333, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29700574

RESUMO

Brain-derived neurotropic factor (BDNF) is a myokine that plays a key role in regulating survival, growth, and maintenance of neurons. We investigated whether the serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Furthermore, we aimed to examine the relationship between this myokine and exercise tolerance. We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. At discharge, the serum BDNF level of all patients was measured using a commercial ELISA kit and they underwent a cardiopulmonary exercise test to measure peak oxygen uptake (peak VO2). Correlation was not observed between BDNF and peak VO2. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization owing to worsening HF was significantly higher in the low BDNF group (p = 0.023). The combination of peak VO2 and BDNF levels led to the identification of subgroups with significantly different probabilities of events (p = 0.005). In particular, in the low BDNF and low peak VO2 group, the frequency of rehospitalization within half a year after discharge was much higher than that in other groups. Multivariate analysis found BDNF as an independent factor of adverse events (hazard ratio 0.956; 95% confidence interval 0.911-0.999; p = 0.046). The serum BDNF level at discharge may be a useful biomarker of the prognosis in patients with HF. Furthermore, combining BDNF and peak VO2 may be useful for predicting early cardiac events.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Tolerância ao Exercício/fisiologia , Insuficiência Cardíaca/fisiopatologia , Consumo de Oxigênio/fisiologia , Volume Sistólico/fisiologia , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências
8.
J Pharmacol Sci ; 136(1): 9-15, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29274665

RESUMO

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease with increased immunoglobulin E (IgE) levels. Activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling is known to occur in the inflammatory regions of AD skin. We previously demonstrated that red ginseng extract (RGE), as an anti-inflammatory agent, had potential for treating AD. However, it is still unclear whether RGE inhibits mTOR/p70S6K signaling. Thus, we examined the anti-inflammatory effects of RGE on IgE or interferon-γ (IFN-γ) induced signaling pathways. In KU812 human basophils, activation of Fcε receptor type Iα (FCεRI), also known as the high affinity IgE receptor, induced phosphorylation of both mTOR and p70S6K. Moreover, levels of phosphorylated p70S6K (p-p70S6K), but not p-mTOR, were decreased by RGE. RGE also decreased p-p70S6K levels in IFN-γ-stimulated human keratinocytes, suppressing the IFN-γ induced increase in levels of C-C chemokine ligand 2 mRNA. Interestingly, the increased p70S6K phosphorylation in skin lesions of AD model mice was attenuated by RGE treatment. In conclusion, RGE is a potential therapy against inflammatory responses involving the p70S6K signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Panax , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Células Cultivadas , Doença Crônica , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Imunoglobulina E , Camundongos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Curr Vasc Pharmacol ; 15(6): 589-598, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28460626

RESUMO

BACKGROUND: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients. OBJECTIVE: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group). RESULTS: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed. CONCLUSION: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.


Assuntos
Capilares/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipóxia/patologia , Indóis/farmacologia , Pirróis/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Capilares/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ventrículos do Coração/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/metabolismo , Marcação In Situ das Extremidades Cortadas/métodos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Hypertens Res ; 40(4): 353-360, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27881852

RESUMO

Hypertension is one of the most important cardiovascular risk factors and results in macrophage infiltration of blood vessels. However, how macrophages coordinate inflammatory responses with endothelial cells (ECs) remains unclear. In this study, we investigated whether exosomes upregulate the expression of inflammatory factors in ECs under hypertensive conditions. Hypertension was induced in rats by continuous infusion of angiotensin II (Ang II). Exosomes were purified from rat serum by density gradient and ultracentrifugation and used to stimulate human coronary artery ECs (HCAECs). Moreover, the interactions between HCAECs and exosomes from human THP-1-derived macrophages were analyzed. Administration of Ang II enhanced the expression of CD68, a macrophage marker, in rat hearts, suggesting enhanced infiltration of macrophages. In addition, the expression of intracellular adhesion molecule-1 (ICAM1) and plasminogen activator inhibitor-1 (PAI-1), a proinflammatory factor, was increased in hypertensive rat hearts compared with control rats. CD68 protein expression and an increase in the expression of some exosome markers were detected in exosomes from hypertensive rat serum. Moreover, the exosomes upregulated the expression levels of ICAM1 and PAI-1 in HCAECs. The level of miR-17, a negative regulator of ICAM1 expression, was markedly decreased in exosomes from hypertensive rat serum compared with exosomes from control rats. Interestingly, Ang II-stimulated THP-1-derived exosomes also enhanced the expression of ICAM1 and PAI-1 and contained reduced levels of miR-17 compared with exosomes from unstimulated cells. These results suggest that inflammation of ECs under hypertensive conditions is caused, at least in part, by macrophage-derived exosomes.


Assuntos
Células Endoteliais/metabolismo , Exossomos/metabolismo , Hipertensão/metabolismo , Macrófagos/metabolismo , Angiotensina II , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Hipertensão/induzido quimicamente , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Ratos Wistar
12.
Cancer Lett ; 378(1): 8-15, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27157913

RESUMO

Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP72/metabolismo , Compostos Organoplatínicos/farmacologia , Proteínas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP72/genética , Humanos , Imunoprecipitação , Espectrometria de Massas , Oxaliplatina , Estabilidade Proteica , Proteínas/genética , Proteólise , Proteômica/métodos , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Transfecção
13.
J Proteomics ; 136: 214-21, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26780229

RESUMO

Heat shock protein 72 (HSP72) is an intracellular molecular chaperone that is overexpressed in tumor cells, and has also been detected in extracellular regions such as the blood. HSP72 forms complexes with peptides and proteins that are released from tumors. Accordingly, certain HSP72-binding proteins/peptides present in the blood of cancer patients may be derived from tumor cells. In this study, to effectively identify low-abundance proteins/peptides in the blood as tumor markers, we established a method for isolating HSP72-binding proteins/peptides from serum. Nine HSP72-specific monoclonal antibodies were conjugated to N-hydroxysulfosuccinimide-activated Sepharose beads (NHq) and used to isolate HSP72 complexes from serum samples. Precipitated proteins were then identified by LC-MS/MS analysis. Notably, this approach enabled the isolation of low-abundance proteins from serum without albumin removal. Moreover, by subjecting the serum samples of ten patients with multiple myeloma (MM) to NHq analysis, we identified 299 proteins present in MM HSP72 complexes, including 65 intracellular proteins. Among the intracellular proteins detected, 21 were present in all serum samples tested, while 11 were detected in both the conditioned media from cultured multiple myeloma cells and serum from MM patients. These results suggest that the NHq method can be applied to discover candidate tumor markers.


Assuntos
Anticorpos Monoclonais/química , Biomarcadores Tumorais , Proteínas Sanguíneas , Proteínas de Choque Térmico HSP72/química , Mieloma Múltiplo/sangue , Proteínas de Neoplasias , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/química , Biomarcadores Tumorais/isolamento & purificação , Proteínas Sanguíneas/química , Proteínas Sanguíneas/isolamento & purificação , Proteínas Sanguíneas/metabolismo , Humanos , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/química , Proteínas de Neoplasias/isolamento & purificação , Ratos , Proteínas Recombinantes/química
14.
Heart Vessels ; 31(9): 1574-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26796134

RESUMO

We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients.


Assuntos
Cardiotônicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Interleucina-11/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Administração Intravenosa , Idoso , Cardiotônicos/administração & dosagem , Angiografia Coronária , Drogas em Investigação/administração & dosagem , Humanos , Interleucina-11/administração & dosagem , Masculino , Contração Miocárdica/efeitos dos fármacos , Intervenção Coronária Percutânea , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
15.
Osaka City Med J ; 61(1): 31-41, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26434103

RESUMO

BACKGROUND: Highly concentrated carbon dioxide (GO2) is useful for treating ischemic diseases. Therefore, we investigated whether treatment with a few micrometers of CO2 molecules, atomized by two fluid nozzles (CO2 mist), could attenuate the development of right ventricular (RV) dysfunction in pulmonary hypertensive rats. METHODS: Six-week-old male Wistar rats were divided into three groups: one that received injected saline; a second that received subcutaneous monocrotaline (MCT; 60 mg/kg) without treatment (PH-UT) group; and a third that received MCT with CO2 mist treatment (PH-CM) after MCT administration. The lower body of each rat was encased in a polyethylene bag, filled with the designated gaseous agent via a gas mist generator, for 30 minutes daily. Hemodynamics and cardiac function were measured at 28 days after beginning MCT administration. Protein levels were measured by western blotting. RESULTS: Rats that received MCT without treatment began to die within 3-4 weeks of the initial administration. However, treatment with CO2 mist extended the survival period of rats in that group. At 28 days after MCT administration, the hemodynamic status, such as the blood pressure and heart rate, involved with left ventricular function, of rats in the PH-UT group were similar to those of rats in the PH-CM group. However, MCT-induced RV weight and RV dysfunction were significantly attenuated by treatment with CO2 mist. Both RV phosphorylated endothelial nitric oxide synthase and heat shock protein 72 levels increased significantly in the PH-CM group, compared to the PH-UT group. CONCLUSIONS: Percutaneous CO2 mist therapy may alleviate RV dysfunction in patients with pulmonary hypertension.


Assuntos
Dióxido de Carbono/administração & dosagem , Fármacos Cardiovasculares/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Monocrotalina , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Aerossóis , Animais , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP72/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Miocárdio/metabolismo , Nebulizadores e Vaporizadores , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Ratos Wistar , Fatores de Tempo , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
16.
J Pharmacol Sci ; 127(4): 474-80, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25906762

RESUMO

Percutaneous treatment with carbon dioxide (CO2) mist, CO2 gas dissolved in water, contributes to improved cardiac function after myocardial infarction (MI). In this study, we investigated the effects of repeated pretreatment with CO2 mist on cardiac dysfunction after MI. The CO2 mist was generated by a dry mist production unit. The whole body of rats below the axilla was wrapped in a polyethylene bag, which was sealed and filled with the CO2 mist in the draft cabinet for 30 min daily for 7 days. MI was induced by ligation of the coronary artery in untreated (UT), CO2 gas-pretreated (CG), and CO2 mist-pretreated (CM) rats. The infarct size and the increase in oxidative stress due to MI were significantly smaller in the CM rats than in the UT rats. Furthermore, the expression of inflammation-related genes, such as monocyte chemoattractant protein-1, and fibrosis-related genes, such as transforming growth factor-ß1, was significantly suppressed in the CM rats. The CM rats had a better left ventricular ejection fraction than the UT rats 7 days after MI. These parameters in the CG rats were the same as in the UT group. Thus, CO2 mist preparative treatment may be potentially useful for the reduction of MI.


Assuntos
Dióxido de Carbono/administração & dosagem , Infarto do Miocárdio/terapia , Administração Tópica , Animais , Dióxido de Carbono/farmacologia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Fibrose/genética , Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Ratos Wistar , Volume Sistólico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Água
17.
J Pharmacol Sci ; 127(2): 181-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25727955

RESUMO

Hypoxia-inducible factors (HIFs) play an important role in the pathogenesis of renal fibrosis. Although the role of macrophage infiltration in the progression of renal fibrosis is well known, the role of macrophage HIF-1 remains to be revealed. To address this question, myeloid specific conditional HIF-1 knock out mice were subjected to unilateral ureteral obstruction (UUO). Renal interstitial deposition of collagen Ⅲ and mRNA expressions of collagen Ⅰ and collagen Ⅲ were markedly increased at 7 days after UUO and myeloid HIF-1 depletion significantly accelerated these increases. Immunohistochemistry and flow cytometric analysis revealed that renal infiltrating macrophages were increased with duration of UUO but myeloid HIF-1 depletion did not affect these changes. Myeloid HIF-1 depletion did not affect M1 and M2 macrophage phenotype polarization in obstructed kidneys. Renal connective tissue growth factor (CTGF) expression was markedly increased and myeloid HIF-1 depletion further enhanced this increase. Immunomagnetic separation of renal cells revealed that renal CTGF was expressed predominantly in renal cells other than macrophages. It is suggested that myeloid HIF-1 attenuates the progression of renal fibrosis in murine obstructive kidney. Alteration of CTGF expression in renal cells other than macrophages is one of possible mechanisms by which myeloid HIF-1 protected renal fibrosis.


Assuntos
Colágeno/metabolismo , Fator 1 Induzível por Hipóxia/fisiologia , Rim/metabolismo , Rim/patologia , Obstrução Ureteral/genética , Animais , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obstrução Ureteral/metabolismo
18.
Int J Cardiol ; 178: 239-46, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25464262

RESUMO

BACKGROUND: Remote ischemic conditioning (RIC) by repeated treatment of transient limb ischemia is a clinically applicable method for protecting the heart against injury at the time of reperfusion. In this study, we investigated the effects of repeated RIC on cardiac dysfunction after myocardial infarction (MI). METHODS AND RESULTS: At 4weeks after MI, rats were separated into the untreated (UT) group or the RIC-treated group. RIC treatment was performed by 5cycles of 5min of bilateral hindlimb ischemia and 5min of reperfusion once a day for 4weeks. Despite comparable MI size, left ventricular (LV) ejection fraction (LVEF) was significantly improved in the RIC group compared with the UT group. Furthermore, the LVEF in the RIC group was improved, although not significantly, after treatment. RIC treatment also prevented the deterioration of LV diastolic function. MI-induced LV interstitial fibrosis in the boundary region and oxidant stress were significantly attenuated by RIC treatment. MicroRNA-29a (miR-29a), a key regulator of tissue fibrosis, was highly expressed in the exosomes and the marginal area of the RIC group. Even in the differentiated C2C12-derived exosomes, miR-29a expression was significantly increased under hypoxic condition. As well as miR-29a, insulin-like growth factor 1 receptor (IGF-1R) was highly expressed both in the exosomes and remote non-infarcted myocardium of the RIC group. IGF-1R expression was also increased in the C2C12-derived exosomes under hypoxic conditions. CONCLUSIONS: Repeated RIC reduces adverse LV remodeling and oxidative stress by MI. Exosome-mediated intercellular communication may contribute to the beneficial effect of RIC treatment.


Assuntos
Comunicação Celular/fisiologia , Exossomos/fisiologia , Insuficiência Cardíaca/terapia , Precondicionamento Isquêmico/métodos , Infarto do Miocárdio/terapia , Remodelação Ventricular/fisiologia , Animais , Doença Crônica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Membro Posterior/irrigação sanguínea , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Wistar , Fatores de Tempo , Função Ventricular Esquerda/fisiologia
19.
J Atheroscler Thromb ; 22(1): 38-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25132376

RESUMO

AIM: Highly concentrated carbon dioxide (CO2) is thought to be useful for ischemic diseases. We investigated whether treatment with a few micrometers of CO2 molecules atomized via two fluidnozzles (CO2 mist) exerts an angiogenic effect in a mouse ischemic hindlimb model. METHODS: Mice with unilateral hindlimb ischemia were divided into untreated (UT), 100% CO2 gas alone-treated (CG), mixed air (O2; 20%, N2; 80%) mist-treated (AM) and 100% CO2 mist-treated (CM) groups. The lower body of the mice was encased in a polyethylene bag filled with each gaseous agent using a gas mist generator for 10 minutes daily. RESULTS: According to a laser Doppler analysis, the ischemic hindlimb blood flow was persistently higher after the seventh day of induction of ischemia in the CM group than in the UT group. The capillary density was also greater in the CM group on day 28 compared with that observed in the UT group. In addition, the parameters in the AM and CG groups were similar to those obtained in the UT group. The observed effects were abolished by the administration of an inhibitor of nitric oxide synthase (NOS). The vascular endothelial growth factor mRNA expression and protein levels and the phosphorylated endothelial NOS level were increased in the CM group compared with that observed in the UT group. A proteomic analysis using liquid chromatography-tandem mass spectrometry identified novel protein candidates regulated by CO2 mist. CONCLUSION: Percutaneous CO2 mist therapy may be useful for treating ischemia-induced angiogenesis.


Assuntos
Dióxido de Carbono/farmacologia , Modelos Animais de Doenças , Membro Posterior/irrigação sanguínea , Isquemia/terapia , Óxido Nítrico Sintase Tipo III/fisiologia , Óxido Nítrico Sintase Tipo II/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Animais , Dióxido de Carbono/administração & dosagem , Hemodinâmica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fosforilação , Ratos Wistar , Vasodilatação
20.
Am J Physiol Heart Circ Physiol ; 307(11): H1626-33, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25281567

RESUMO

The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 µm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, ß-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea.


Assuntos
Cardiomiopatias/patologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hidrogênio/farmacologia , Hipóxia/patologia , Remodelação Ventricular/efeitos dos fármacos , Aldeídos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cricetinae , Inibidores de Cisteína Proteinase/farmacologia , Gases , Ventrículos do Coração/efeitos dos fármacos , Mesocricetus , Tamanho do Órgão/efeitos dos fármacos , Superóxidos/metabolismo , Ultrassonografia
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