RESUMO
PURPOSE: Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. METHODS: In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. RESULTS: OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. CONCLUSION: Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.
Assuntos
Calcitriol/análogos & derivados , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Insuficiência Renal/complicações , Idoso , Animais , Calcineurina/efeitos dos fármacos , Calcitriol/farmacologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Gravidez , Ratos , Ratos Wistar , Estudos RetrospectivosRESUMO
RATIONALE: Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. OBJECTIVE: We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. METHODS AND RESULTS: We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. CONCLUSIONS: Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.
Assuntos
Doxorrubicina/toxicidade , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Antineoplásicos/toxicidade , Células Cultivadas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos ICR , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenilbutiratos/uso terapêutico , RatosRESUMO
For atherosclerotic cardiovascular diseases (ACD), gene therapy may be a potential therapeutic strategy; however, lack of effective and safe methods for gene delivery to atherosclerotic plaques have limited its potential therapeutic applications. To overcome this limitation, we developed a novel antibody-based gene delivery system (anti-HB-EGF/NA vector) by chemically crosslinking antibodies against human heparin-binding epidermal growth factor-like growth factor (HB-EGF). It has been shown to be excessively expressed in human atherosclerotic plaques and NeutrAvidin (NA) for conjugating biotinylated siRNA. Immunofluorescence staining and quantitative flow cytometry analysis using human HB-EGF-expressing cells showed both antibody-mediated selective cellular targeting and efficient intracellular delivery of conjugated biotin-fluorescence. Moreover, we demonstrated antibody-mediated significant and selective gene knockdown via conjugation with anti-HB-EGF/NA vector and biotinylated siRNA (anti-HB-EGF/NA/b-siRNA) in vitro. Furthermore, using high fat-fed human HB-EGF knock-in and apolipoprotein E-knockout (Hbegf hz/hz; Apoe-/-) mice, we demonstrated that the anti-HB-EGF/NA vector, conjugating biotin-fluorescence, increasingly accumulated within the atherosclerotic plaques of the ascending aorta in which human HB-EGF expression levels were highly elevated. Moreover, in response to a single intravenous injection of anti-HB-EGF/NA/b-siRNA in a dose-dependent manner, qPCR analysis of laser-dissected atherosclerotic plaques of the ascending aorta showed significant knockdown of the reporter gene expression. These results suggest that the anti-HB-EGF antibody-mediated siRNA delivery could be a promising delivery system for gene therapy of ACD.
Assuntos
Anticorpos/uso terapêutico , Aterosclerose/terapia , Avidina/imunologia , Terapia Genética/métodos , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , RNA Interferente Pequeno/uso terapêutico , Animais , Aterosclerose/metabolismo , Humanos , Camundongos , Camundongos Knockout , Resultado do TratamentoRESUMO
There are few methods available for injectable liposome production under good manufacturing practices (GMP). Injectable liposome production processes under GMP generally consist of liposome formation, size homogenization, organic solvent removal, liposome concentration control and sterilization. However, these complicated and separate processes make it difficult to maintain scalability, reproducibility and sterility. To overcome these limitations, we developed a novel one-step in-line closed liposome production system that integrated all production processes by combining the in-line thermal mixing device with modified counterflow dialysis. To validate the system, we produced liposomal cyclosporine A (Lipo-CsA) and lyophilized the liposomes. The three independent pilot batches were highly reproducible and passed the quality specifications for injectable drugs, demonstrating that this system could be used under GMP. The accelerated stability test suggested that the liposomes would be stable in long-term storage. This one-step system facilitates a fully automated and unattended production of injectable liposomes under GMP.
Assuntos
Antifúngicos/administração & dosagem , Ciclosporina/administração & dosagem , Composição de Medicamentos/métodos , Lipossomos/química , 2-Propanol/química , Antifúngicos/química , Ciclosporina/química , Composição de Medicamentos/instrumentação , Estabilidade de Medicamentos , Desenho de Equipamento , Liofilização/métodos , Injeções , Lipossomos/ultraestrutura , Tamanho da PartículaRESUMO
The tsunami caused by the Great East Japan Earthquake on March 11, 2011 disturbed coastal environments in the eastern Tohoku region in Japan. Numerous terrestrial materials, including anthropogenic organic compounds, were deposited in the coastal zone. To evaluate the impacts of the disaster, we analyzed PCBs, LABs, PAHs, and hopanes in mussels collected from 12 locations in the east of Tohoku during 2011-2015 (series A) by GC-ECD or GC-MS and compared them with results from mussels collected from 22 locations around Japan during 2001-2004 (series B). Early LAB concentrations in series A at some locations were higher than the maximum concentrations in series B but decreased during the 5 years. Because LABs are molecular markers for sewage, these decreases are consistent with the recovery of sewage treatment plants in these areas. Early PAH concentrations at several locations were higher than the maximum concentrations in series B but also decreased. These high concentrations would have been derived from oil spills. The decreases of both LABs and PAHs indicate that these locations were affected by the tsunami but recovered. In contrast, later high concentrations of target compounds were detected sporadically at several locations. This pattern suggests that environmental pollution was caused by human activities, such as reconstruction. To understand the long-term trend of environmental pollution induced by the disaster, continuous monitoring along the Tohoku coast is required.
Assuntos
Terremotos , Monitoramento Ambiental , Poluentes Ambientais/análise , Japão , Bifenilos Policlorados/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Análise Espaço-Temporal , TsunamisRESUMO
PURPOSE: Although amiodarone is recognized as the most effective anti-arrhythmic drug available, it has negative hemodynamic effects. Nano-sized liposomes can accumulate in and selectively deliver drugs to ischemic/reperfused (I/R) myocardium, which may augment drug effects and reduce side effects. We investigated the effects of liposomal amiodarone on lethal arrhythmias and hemodynamic parameters in an ischemia/reperfusion rat model. METHODS AND RESULTS: We prepared liposomal amiodarone (mean diameter: 113 ± 8 nm) by a thin-film method. The left coronary artery of experimental rats was occluded for 5 min followed by reperfusion. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads accumulated in the I/R myocardium. Amiodarone was measurable in samples from the I/R myocardium when liposomal amiodarone, but not amiodarone, was administered. Although the intravenous administration of amiodarone (3 mg/kg) or liposomal amiodarone (3 mg/kg) reduced heart rate and systolic blood pressure compared with saline, the decrease in heart rate or systolic blood pressure caused by liposomal amiodarone was smaller compared with a corresponding dose of free amiodarone. The intravenous administration of liposomal amiodarone (3 mg/kg), but not free amiodarone (3 mg/kg), 5 min before ischemia showed a significantly reduced duration of lethal arrhythmias (18 ± 9 s) and mortality (0 %) during the reperfusion period compared with saline (195 ± 42 s, 71 %, respectively). CONCLUSIONS: Targeting the delivery of liposomal amiodarone to ischemic/reperfused myocardium reduces the mortality due to lethal arrhythmia and the negative hemodynamic changes caused by amiodarone. Nano-size liposomes may be a promising drug delivery system for targeting I/R myocardium with cardioprotective agents.
Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Amiodarona/sangue , Amiodarona/farmacocinética , Animais , Antiarrítmicos/sangue , Antiarrítmicos/farmacocinética , Arritmias Cardíacas/sangue , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Lipossomos , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/administração & dosagem , Ratos , Ratos WistarRESUMO
BACKGROUND: Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified. METHODS AND RESULTS: In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2alpha, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts. CONCLUSIONS: We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Insuficiência Cardíaca/genética , Animais , Apoptose/fisiologia , Proteínas Estimuladoras de Ligação a CCAAT/deficiência , Cardiomiopatias/patologia , Cardiomiopatias/cirurgia , Primers do DNA , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Volume SistólicoRESUMO
The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Miócitos Cardíacos/citologia , Peptídeo Natriurético Encefálico/biossíntese , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Humanos , Microscopia Confocal/métodos , Miocárdio/metabolismo , Regiões Promotoras Genéticas , Interferência de RNA , Ratos , Fatores de Transcrição de Fator Regulador X , Proteína 1 de Ligação a X-BoxRESUMO
Thirteen isomers of branched para-nonylphenols (para-NP) in three technical mixtures were isomer-specifically determined using their synthesized standards by SIM of structurally specific ions, m/z 135, 149 or 163 with GC-MS. Of the 13 isomers, four isomers, 4-(2,4-dimethylheptan-4-yl)phenol, 4-(4-methyloctan-4-yl)phenol, 4-(3-ethyl-2-methylhexan-2-yl)phenol (3E22NP) and 4-(2,3-dimethylheptan-2-yl)phenol synthesized for their determinations were first used as standard substances. The 13 isomers in the technical mixtures individually occurred at mass percent portion of more than 2%. The total mass percent portions in the mixtures from Tokyo Chemical Industry (TCI), Aldrich, and Fluka covered with 89+/-2%, 75+/-4% and 77+/-2%, respectively. The abundance of 4-(3,6-dimethylheptan-3-yl)phenol in the three mixtures was the largest with 11.1+/-2% to 9.9+/-0.3%, while that of 4-(2-methyloctan-2-yl)phenol was the smallest with 2.9+/-0.3% to 3.0+/-0.2%. Additionally, structures of four new isomers of more than 1% portion present in a technical mixture were elucidated as two pairs of diastereomeric isomers: two types of 4-(3,4-dimethylheptan-4-yl)phenol (344NP) and those of 4-(3,4-dimethylheptan-3-yl)phenol (343NP). By estrogenic assay of 13 isomers with yeast estrogen screen system, the activity of 3E22NP was the highest, while that of 4-(3-methyloctan-3-yl)phenol was the least. Their relative activities to that of 3E22NP were individually calculated. Estrogenic equivalent concentrations of the three technical mixtures were predictively evaluated. The ratio of the EEC to the conventional concentration, total mass percent portions of the 13 isomers in technical mixtures were 0.208 for TCI, 0.206 for Aldrich and 0.205 for Fluka. The predicted estrogenic activity of measured concentration of para-NP in technical mixtures was approximately 5-fold greater than the measured estrogen agonist activity.
Assuntos
Estrogênios/análise , Estrogênios/metabolismo , Fenóis/análise , Fenóis/metabolismo , Receptores de Estrogênio/metabolismo , Estrogênios/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Isomerismo , Fenóis/química , Receptores de Estrogênio/genética , Padrões de Referência , Leveduras/genética , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Statins have pleiotropic effects, such as improvement in endothelial function and antiinflammatory, antiproliferative, and antioxidative effects, that should be beneficial for patients with chronic heart failure (CHF). The aim of this study was to investigate the long-term effect of statins on neurohumoral activation and cardiac function in patients with CHF. METHODS: We enrolled 38 outpatients with mild to moderate CHF and radionuclide left ventricular ejection fraction (LVEF) <40%. These patients were randomly assigned to receive atorvastatin (10 mg/d) or conventional treatment for heart failure and were prospectively followed up for at least 3 years. At entry, we measured plasma concentrations of brain natriuretic peptides (BNPs) and left ventricular end-diastolic dimension and LVEF by echocardiography; thereafter, these measurements were repeated at least every 6 months. The primary end point was defined as the improvement in cardiac function and BNP. RESULTS: There were no significant differences in age, sex, New York Heart Association class, left ventricular end-diastolic dimension, LVEF, and serum cholesterol level at entry between patients with (n = 19) and without atorvastatin (control, n = 19). After a follow-up period of 31 +/- 14 months, BNP (median [25th, 75th percentile]) significantly decreased in the atorvastatin group (84 [36, 186] to 55 [37, 91] pg/mL, P = .02) but not in the control group. Left ventricular end-diastolic dimension significantly decreased (67.1 [59.9, 70.8] to 61.1 [58, 63.9] mm, P = .02), and LVEF also significantly increased in the atorvastatin group (33.3% +/- 7.4% to 39.1% +/- 12.1%, P = .01) but not in the control group. CONCLUSION: Long-term atorvastatin therapy decreases neurohumoral activation and improves cardiac function in patients with mild to moderate CHF.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeo Natriurético Encefálico/metabolismo , Pirróis/uso terapêutico , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Atorvastatina , Fator Natriurético Atrial/metabolismo , Intervalo Livre de Doença , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologiaRESUMO
In the case of an emergency coronary procedure where the risk of contrast-induced nephropathy is especially high, there are few reliable methods to attenuate renal injury. We examined the efficacy of sodium bicarbonate for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure. We enrolled 59 patients who were scheduled to undergo an emergency coronary angiography or intervention. These patients were randomized to receive a 154-mEq/L infusion of sodium bicarbonate (n = 30) or sodium chloride (n = 29), as a bolus of 3 ml/kg/hour for 1 hour before the administration of contrast, followed by an infusion of 1 ml/kg/hour for 6 hours during and after the procedure. In the sodium bicarbonate group, serum creatinine concentration remained unchanged within 2 days of contrast administration (1.31 +/- 0.52 to 1.31 +/- 0.59 mg/dl), whereas it increased in the sodium chloride group (1.32 +/- 0.65 to 1.52 +/- 0.92 mg/dl, p = 0.01). The incidence of contrast-induced nephropathy (an increase >0.5 mg/dl or >25% in serum creatinine concentration within 2 days of contrast) was significantly lower in the sodium bicarbonate group than in the sodium chloride group (7% vs 35%, p = 0.01, risk ratio 0.19, 95% confidence interval 0.046 to 0.80). In conclusion, hydration with sodium bicarbonate is more effective than with sodium chloride for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure.
Assuntos
Angioplastia Coronária com Balão , Meios de Contraste/efeitos adversos , Angiografia Coronária , Hidratação , Nefropatias/prevenção & controle , Bicarbonato de Sódio/uso terapêutico , Cloreto de Sódio/uso terapêutico , Idoso , Creatinina/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Iopamidol/efeitos adversos , Nefropatias/induzido quimicamente , Masculino , Fatores de Risco , Bicarbonato de Sódio/administração & dosagem , Cloreto de Sódio/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: ST2 is one of the interleukin (IL)-1 receptor family members comprising of membrane-bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non-ischemic HF. Here, we tested whether IL-33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL-33-/-) mice. METHODS AND RESULTS: Transverse aortic constriction (TAC)/sham surgery were carried out in both IL-33 and WT-littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF-α were enhanced in IL-33-/- mice than in WT mice. After 8-weeks, IL-33-/- mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c-Myc/BNP) molecular markers were also significantly enhanced in IL-33-/- mice than those in WT mice. CONCLUSIONS: We report for the first time that ablation of IL-33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL-33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL-33 in non-ischemic HF.
Assuntos
Remodelamento Atrial , Modelos Animais de Doenças , Insuficiência Cardíaca/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/agonistas , Interleucina-33/metabolismo , Miocárdio/metabolismo , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Fibrose , Regulação da Expressão Gênica , Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Ligantes , Camundongos , Camundongos Knockout , Miocárdio/imunologia , Miocárdio/patologia , RNA Mensageiro/metabolismo , Análise de Sobrevida , Células Th1/imunologia , Células Th1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Statins have pleiotropic effects such as anti-inflammatory and vascular protective effects that would be beneficial for patients with chronic heart failure. This report describes a patient with idiopathic dilated cardiomyopathy and a long-standing history of heart failure that was treated with atorvastatin in addition to conventional therapy that included beta-blockers. Atorvastatin therapy for 12 months was associated with an improvement in cardiac function and improved left ventricular remodeling and peak oxygen consumption. This result suggests that statin therapy may be a potential novel treatment strategy for patients with chronic heart failure.
Assuntos
Cardiomiopatia Dilatada/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Adulto , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Humanos , Hipercolesterolemia/tratamento farmacológico , MasculinoRESUMO
Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Imunossupressores/farmacologia , Lipossomos/administração & dosagem , Miocardite/tratamento farmacológico , Nanopartículas/administração & dosagem , Tacrolimo/farmacologia , Doença Aguda , Animais , Doenças Autoimunes/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imunossupressores/administração & dosagem , Lipossomos/química , Masculino , Miocardite/metabolismo , Nanopartículas/química , Ratos , Ratos Endogâmicos Lew , Tacrolimo/administração & dosagemRESUMO
Concentrations of polychlorinated biphenyls (PCBs) in beached resin pellets were examined to reveal variability between individual particles and differences among beaches. Fifty-five resin pellets from a beach in Tokyo were individually analyzed for PCBs, and showed concentrations ranging from <28 to 2,300 ng/g. This indicates that concentrations are highly variable between particles. Among several characters, discoloration (e.g., yellowing) had a positive relationship with PCB concentration: discolored pellets contained more PCBs than others on most of the beaches sampled. Given the color-selective ingestion of food by some organisms, this may be ecotoxicologically important. Measurements of samples from 47 beaches in Japan showed regional differences in PCB concentrations in resin pellets consistent with those in mussels. Sporadic high concentrations of PCBs were also found in pellets from remote islands, suggesting that resin pellets could be the dominant route of exposure to the contaminants at remote sites. The similarity of PCB concentrations between resin pellets and mussels suggests a potential use of resin pellets to monitor pollution in seawater.
Assuntos
Praias , Monitoramento Ambiental/estatística & dados numéricos , Bifenilos Policlorados/análise , Resinas Sintéticas/química , Varredura Diferencial de Calorimetria , Monitoramento Ambiental/métodos , Japão , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
AIMS: We previously reported the association of single nucleotide polymorphisms in the lymphotoxin alpha (LTα) gene with susceptibility to acute myocardial infarction (AMI) and increased mortality after discharge. In the present study, we investigated whether the adverse effect of LTα C804A polymorphism on mortality could be pharmacologically modified by statin treatment after AMI. METHODS AND RESULTS: We conducted a multicenter study that included 3486 post-AMI patients between 1998 and 2008. During a median follow-up period of 1775 days, 247 deaths were recorded. The mortality rate was significantly higher in LTα 804A allele carriers compared to non-804A allele carriers (7.9% vs. 5.7%, p = 0.011). The LTα 804A allele was significantly associated with increased mortality for post-AMI patients not receiving statins (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.03-2.12, p = 0.034), but not for those receiving statins (HR: 1.22, 95% CI: 0.70-2.10, p = 0.486). In-vitro experimental analyses demonstrated that the LTα 804A polymorphic protein, 26Asn-LTα3, induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LTα3 804C polymorphic protein 26Thr-LTα3. However, the effects of both LTα3 proteins were decreased and became comparable by the pretreatment of cells with pravastatin. CONCLUSION: LTα C804A polymorphism was associated with an increased risk of mortality for AMI patients, although this effect was masked in patients treated with statins. This finding is supported by the observed attenuation of 26Asn-LTα3-mediated monocyte-endothelial interaction and ER stress in cardiomyocytes treated with pravastatin. LTα C804A polymorphism may have potential as a novel therapeutic target for secondary prevention after AMI.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Linfotoxina-alfa/genética , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Polimorfismo de Nucleotídeo Único , Pravastatina/uso terapêutico , Doença Aguda , Idoso , Alelos , Animais , Adesão Celular , Movimento Celular , Retículo Endoplasmático/metabolismo , Feminino , Seguimentos , Heterozigoto , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Modelos de Riscos Proporcionais , Ratos , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
OBJECTIVES: We prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG), heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF). BACKGROUND: Cardiac MIBG imaging predicts prognosis of CHF patients. However, the long-term predictive value of MIBG imaging for SCD in this population remains to be elucidated. METHODS: At entry, cardiac MIBG imaging, SAECG, 24-h Holter monitoring, and standard 12-lead electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients with a radionuclide left ventricular ejection fraction (LVEF) <40%. The cardiac MIBG washout rate (WR) was obtained from MIBG imaging. Furthermore, the time and frequency domain HRV parameters were calculated from 24-h Holter recordings, and QT dispersion was measured from the 12-lead ECG. RESULTS: During a follow-up period of 65 +/- 31 months, 18 of 106 patients died suddenly. A multivariate Cox analysis revealed that WR and LVEF were significantly and independently associated with SCD, whereas the SAECG, HRV parameters, or QT dispersion were not. Patients with an abnormal WR (>27%) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95% confidence interval: 1.55 to 14.76). Even when confined to the patients with LVEF >35%, SCD was significantly more frequently observed in the patients with than without an abnormal WR (p = 0.02). CONCLUSIONS: Cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.
Assuntos
3-Iodobenzilguanidina , Morte Súbita Cardíaca/prevenção & controle , Insuficiência Cardíaca Sistólica/diagnóstico por imagem , Compostos Radiofarmacêuticos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Idoso , Doença Crônica , Eletrocardiografia Ambulatorial , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Cintilografia , Índice de Gravidade de Doença , Volume SistólicoRESUMO
Samples of polyethylene pellets were collected at 30 beaches from 17 countries and analyzed for organochlorine compounds. PCB concentrations in the pellets were highest on US coasts, followed by western Europe and Japan, and were lower in tropical Asia, southern Africa and Australia. This spatial pattern reflected regional differences in the usage of PCBs and was positively correlated with data from Mussel Watch, another monitoring approach. DDTs showed high concentrations on the US west coast and in Vietnam. In Vietnam, DDT was predominant over its metabolites (DDE and DDD), suggesting the principal source may be current usage of the pesticide for malaria control. High concentrations of pesticide HCHs were detected in the pellets from southern Africa, suggesting current usage of the pesticides in southern Africa. This study demonstrates the utility and feasibility of the International Pellet Watch approach to monitor POPs at a global scale.