RESUMO
AIM: Pentraxin 3 (PTX3) is a novel marker for the primary local activation of innate immunity and inflammatory responses. Although clinical and experimental evidence suggests that PTX3 is associated with atherosclerosis, the relationship between PTX3 and vascular remodeling after wall injury remains to be determined. We investigated the effects of PTX3 on neointimal hyperplasia following wire vascular injury. METHODS: PTX3 systemic knockout (PTX3-KO) mice and wild-type littermate (WT) mice were subjected to wire-mediated endovascular injury. At four weeks after wire-mediated injury, the areas of neointimal and medial hyperplasia were evaluated. RESULTS: The PTX3-KO mice exhibited higher hyperplasia/media ratios than the WT mice after wire injury, and the degree of Mac-3-positive macrophage accumulation was significantly higher in the PTX3-KO mice than in the WT mice. Furthermore, the PTX3-KO mice showed a much greater increase in the number of PCNA-stained cells in the vascular wall than that observed in the WT mice. CONCLUSIONS: A deficiency of PTX3 results in deteriorated neointimal hyperplasia after vascular injury via the effects of macrophage accumulation and vascular smooth muscle cell proliferation and migration.
Assuntos
Proteína C-Reativa/fisiologia , Proliferação de Células , Hiperplasia/etiologia , Macrófagos/patologia , Músculo Liso Vascular/patologia , Neointima/etiologia , Proteínas do Tecido Nervoso/fisiologia , Lesões do Sistema Vascular/complicações , Animais , Movimento Celular , Hiperplasia/metabolismo , Hiperplasia/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Neointima/metabolismo , Neointima/patologia , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologiaRESUMO
Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal for the preservation of myocardial function. However, reperfusion itself causes additional myocardium injuries. Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in the cardioprotective effects occurring after ischemia/reperfusion (I/R). DAG kinase (DGK) controls cellular DAG levels by converting DAG to phosphatidic acid, and may act as an endogenous regulator of DAG-PKC signaling. In the present study, we examined the functional role of DGKα in cardiac injury after I/R in in vivo mouse hearts. We generated transgenic mice with cardiac-specific overexpression of DGKα (DGKα-TG). The left anterior descending coronary artery was transiently occluded for 20 min and reperfused for 24 h in DGKα-TG mice and wild-type littermate (WT) mice. The levels of phosphorylation activity of PKCε, extracellular-signal regulated kinase (ERK) 1/2, and p70 ribosomal S6 kinase (p70S6K) were increased after I/R in WT mouse hearts. However, in DGKα-TG mice, activation of PKCε, ERK1/2, and p70S6K was attenuated compared to WT mice. After 24 h, Evans blue/triphenyltetrazolium chloride double staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that DGKα-TG mice had significantly larger myocardial infarctions and larger numbers of TUNEL-positive cardiomyocytes than WT mice. Echocardiography and cardiac catheterization revealed that left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice after I/R. These findings suggest that DGKα exacerbates I/R injury by inhibiting the cardioprotective effects of PKCε, ERK1/2, and p70S6K activation.
Assuntos
Diacilglicerol Quinase/metabolismo , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Miocárdio/enzimologia , Animais , Apoptose , Diacilglicerol Quinase/genética , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fosforilação , Proteína Quinase C-épsilon/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sístole , Função Ventricular Esquerda , Pressão VentricularRESUMO
Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
Assuntos
Fibrilação Atrial/complicações , Células Endoteliais/metabolismo , Insuficiência Cardíaca/complicações , Trombose/etiologia , Receptor 4 Toll-Like/metabolismo , Animais , Fibrilação Atrial/sangue , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , Chaperonina 60/metabolismo , Modelos Animais de Doenças , Átrios do Coração/metabolismo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais , Trombose/sangue , Trombose/genética , Trombose/metabolismo , Trombose/fisiopatologia , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Left ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload. METHODS AND RESULTS: PTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice. CONCLUSION: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.
Assuntos
Aorta/metabolismo , Proteína C-Reativa/metabolismo , Constrição Patológica/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Aorta/diagnóstico por imagem , Aorta/patologia , Proteína C-Reativa/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Constrição Patológica/genética , Constrição Patológica/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologiaRESUMO
BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) proteolyzes insulin-like growth factor (IGF)-binding proteins and thus increases IGF-1 bioactivity. PAPP-A has been reported to be involved in various pathophysiologic abnormalities; however, the clinical significance of PAPP-A has not been examined in cases of heart failure (HF). We hypothesized that PAPP-A levels might be correlated with the severity of HF. METHODS AND RESULTS: PAPP-A and B-type natriuretic peptide (BNP) levels were measured in 262 subjects (182 HF patients and 80 control subjects). PAPP-A levels were higher in patients with HF than in control subjects and increased with advancing New York Heart Association functional class. There were 53 cardiac events during a mean follow-up period of 796 days. PAPP-A levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 3 groups on the basis of their PAPP-A and BNP levels. Kaplan-Meier analysis demonstrated that the group with both high BNP with high PAPP-A had a significantly higher cardiac event rate than other groups. CONCLUSIONS: Serum PAPP-A levels were related to the severity of HF and associated with a high risk for adverse cardiac events in HF patients, suggesting that PAPP-A might be involved in the pathogenesis of HF.
Assuntos
Insuficiência Cardíaca/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Proteína Plasmática A Associada à Gravidez/metabolismo , Idoso , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Humanos , Japão , Valor Preditivo dos Testes , Curva ROC , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
BACKGROUND: DNA in the nucleus is one of the major targets of reactive oxygen species (ROS), and oxidative DNA damage has been implicated in the pathogenesis of chronic heart failure. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is produced from deoxyguanosine in DNA by ROS. The purpose of this present study was to examine the clinical significance of serum 8-OHdG levels in patients with heart failure. METHODS: We measured serum 8-OHdG levels in 230 patients with chronic heart failure and 42 control subjects without heart failure by sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 472 days with the end points of cardiac death or progressive heart failure requiring re-hospitalization. RESULTS: Serum 8-OHdG concentrations were higher in patients with heart failure than in control subjects (P < 0·001) and increased with advancing New York Heart Association (NYHA) functional class (P < 0·001). Normal upper limit of 8-OHdG level was determined as mean ± 2SD value from 42 control subjects (0·40 ng mL(-1)). Abnormally high serum 8-OHdG levels (> 0·40 ng mL(-1)) were observed in 21·2%, 43·1%, 42·6% and 69·4% through NYHA I to IV (P < 0·001). A total of 66 cardiac events occurred during a follow-up period, and Kaplan-Meier survival curves demonstrated that cardiac event rate was markedly higher in patients with high 8-OHdG levels than in those with normal 8-OHdG levels (62·4% vs. 29·6%, P = 0·0007). CONCLUSIONS: Serum 8-OHdG levels provide important prognostic information for the risk stratification of patients with heart failure.
Assuntos
Desoxiguanosina/análogos & derivados , Insuficiência Cardíaca/sangue , 8-Hidroxi-2'-Desoxiguanosina , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Desoxiguanosina/sangue , Progressão da Doença , Métodos Epidemiológicos , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , UltrassonografiaRESUMO
OBJECTIVE: Iodine-123-metaiodobenzylguanidine ((123)I-MIBG) has been used to assess the function of the cardiac sympathetic nervous system in patients with chronic heart failure (HF). The usefulness of (123)I-MIBG imaging for evaluating patients with heart failure with preserved ejection fraction (HFPEF) has not been established. METHODS: We performed (123)I-MIBG scintigraphy and echocardiography and measured the plasma brain natriuretic peptide (BNP) levels of 117 consecutive HF patients (64 men, mean age 66 ± 14 years) with a left ventricular ejection fraction (LVEF) of ≥50% who were admitted to our hospital. Patients were divided into 2 groups according to the New York Heart Association (NYHA) functional class. RESULTS: The (123)I-MIBG delayed heart-to-mediastinum (H/M) ratio was significantly lower, and the washout rate (WR) was higher in patients with HFPEF with advanced NYHA functional class (NYHA functional class I and II vs. III: 1.90 ± 0.34 vs. 1.49 ± 0.32, p < 0.0001; 25.9 ± 13.4 vs. 46.9 ± 16.3%, p < 0.0001, respectively). On the other hand, the (123)I-MIBG WR was not correlated with LVEF and had a weak correlation with plasma BNP levels (R = 0.207, p = 0.0346). Moreover, patients with a high (123)I-MIBG WR showed a poor clinical outcome (p = 0.0033). CONCLUSIONS: (123)I-MIBG imaging provides independent prognostic information in patients with HFPEF.
Assuntos
3-Iodobenzilguanidina , Diagnóstico por Imagem , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico , 3-Iodobenzilguanidina/farmacocinética , Idoso , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Prognóstico , RiscoRESUMO
BACKGROUND: Midkine, a heparin-binding growth factor, has various functions such as migration of inflammatory cell and anti-apoptotic effect. Invasion of inflammatory cell and cardiomyocyte apoptosis are involved in development and progression of heart failure (HF). However, the relationship between midkine and HF has not been previously examined. Therefore, we examined clinical significance of serum midkine levels to determine the prognosis of HF patients. METHODS AND RESULTS: Serum levels of midkine were measured at admission in 216 consecutive patients hospitalized for HF and 60 control subjects. Patients were prospectively followed during a mean follow-up period of 653 +/- 375 days with the end points of cardiac death and progressive HF requiring rehospitalization. Serum concentrations of midkine were significantly higher in patients with HF than in controls. Patients with cardiac events had significantly higher concentrations of midkine than those without cardiac events. Kaplan-Meier analysis revealed that cardiac event rates increased markedly as midkine levels rose. Furthermore in the multivariate analysis, after adjustment for age, gender ,and complications, midkine was the independent predictor of cardiac events. CONCLUSION: Serum midkine levels are increased in HF patients, and midkine is a novel marker for risk stratifying HF patients.
Assuntos
Citocinas/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Doença Crônica , Diástole/fisiologia , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Midkina , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Taxa de Sobrevida/tendências , Sístole/fisiologia , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Serum neopterin concentration was measured in 198 patients with chronic heart failure (CHF) and 62 control subjects by ELISA. Patients were prospectively followed during a median follow-up period of 745 days with end points of cardiac death or re-hospitalization due to progressive heart failure. Serum concentration of neopterin increased with advancing New York Heart Association (NYHA) functional class (P<0.001). High neopterin group had a significantly higher incidence of cardiac events than low neopterin group (P<0.0001). In the multivariate Cox analysis, serum neopterin concentration was an independent risk factor for cardiac events (hazard ratio 1.70, 95%CI 1.16-2.50, P=0.0068). Serum neopterin concentration is a novel prognostic marker for CHF.