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Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.
Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.
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Abstract Background In the current era, there is always search for better cardiovascular biomarkers to early diagnose the disease. Objectives We aimed to investigate the association between a novel biomarker, cardiothropin-1 (CT-1), and standard markers of myocardial ischemia in patients with acute coronary syndrome (ACS) in Turkey. Patients and Methods In this prospective cohort study, patients who were admitted to our institution between July 2012 and July 2013 with the diagnosis of ACS were included. The standard markers of myocardial necrosis and CT-1 were evaluated at the time of admission and after 6 hours. Changes in laboratory parameters were statistically tested and correlated with routinely used markers of myocardial ischemia. The distribution of the data was analyzed by the Kolmogorov-Smirnov test. Proportional analysis and changes in laboratory parameters were evaluated with Chi-Square test and Fisher Exact test. Statistical significance was defined as p<0.05. Results The study enrolled 24 patients (14 male, 10 female) with ST-segment elevation myocardial infarction (STEMI) and 16 patients (9 male, 7 female) with non-ST-segment elevation myocardial infarction (NSTEMI) with elevated cardiac enzymes such as creatine kinase (CK), creatine kinase-MB (CK-MB) and Troponin-T (Tn-T). The average age of the patients was 61.45 ± 11.04 years. Increasing CT-1 levels were correlated with the increasing CK (p=0.035 and p=0.018, respectively), CK-MB (p=0.006 and p=0.096, respectively), and Tn-T (p=0.041 and p=0.000, respectively) at first and at the 6th hour measurements. The CT-1 values were found to be more increased in the STEMI group (p=0.0074). Conclusion CT-1 is one of the novel biomarkers for cardiac injury. It is correlated with standard markers of myocardial ischemia and the results suggest that CT-1 can be used as a new biomarker.
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Humans , Male , Female , Middle Aged , Aged , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/blood , Myocardial Infarction/diagnosis , Myocardial Infarction/blood , Atrial Fibrillation , Biomarkers , Prospective Studies , Troponin T , Creatine KinaseABSTRACT
Cardiotrophin-1 (CT-1) is an important regulator of organ protection and glucose and lipid metabolism. Aims: To explore the role of hypoxia-inducible factors (HIFs) in regulating CT-1 expression in cholestatic disease. Methods: Twenty-three pediatric biliary atresia patients and 7 healthy liver donors were enrolled from Jun. 2016 to Jun. 2017 at Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Cellular localization and expressions of HIF-1α, HIF-2α and CT-1 in liver tissue were detected by immunohistochemistry and Western blotting. In in vitro study, human umbilical vein endothelial cells (HUVECs) were treated with H2O2, a strong oxidizer, with or without silencing the expression of HIF-2α with RNA interference, and the expressions of HIF-2α and CT-1 were determined by Western blotting and real-time PCR. Results: In pediatric cholestatic liver tissue, HIF-2α and CT-1 were co-distributed in cholangiocytes and stromal cells such as vascular endothelial cells and inflammatory cells, while HIF-1α was only expressed in some inflammatory cells occasionally. Western blotting showed elevated expressions of HIF-2α and CT-1 in pediatric cholestatic liver tissue when compared with that of healthy controls. H2O2-induced oxidative stress could significantly increase the expressions of HIF-2α and CT-1 in HUVECs, while silencing of HIF-2α could significantly decrease the transcription of CT-1 induced by H2O2. Conclusions: HIF-2α but not HIF-1α regulates the expression of CT-1 in pediatric cholestatic disease. In cholestasis, oxidative stress may induce CT-1 expression via HIF-2α-dependent pathway.
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Objective: To investigate the efficacy of sodium creatine phosphate in the treatment of acute left heart failure caused by essential hypertension, and observe the changes of serum cytochrome C (Cyt C) and cardiotrophin-1 (CT-1). Methods: Seventy-three patients with essential hypertension complicated with acute left heart failure were randomly divided into the control group (n=35) and the observation group (n=38). The patients in the control group were given such treatment as oxygen uptake, diuresis, hypotension and dilatation of blood vessels. The patients in the observation group were given sodium creatine phosphate (1. 0mg, ivd, qd) on the basis of the control group. The changes of NYHA functional class, 6-minute walking distance and left ventricular ejection fraction (LVEF% ) before the treatment, 3 days and 7 days after the treatment were observed. The serum levels of NT-proBNP, ST2, Cyt C and CT-1 were measured by ELISA before the treatment and 3 days and 7 days after the treatment. Results: Compared with those be-fore the treatment, the cardiac function indices were improved after the treatment, and the levels of serum NT-proBNP, ST2, Cyt C and CT-1 all decreased (P<0. 05). Conclusion: Creatine sodium phosphate can effectively enhance the clinical efficacy in hypertension patients with acute left heart failure. The mechanism may be related to enhancing the energy metabolism of myocardial cells and reduc-ing cardiomyocyte apoptosis.
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Objective To investigate the effect of cardiotrophin-1 (CT-1) mediated by recombinant adenovirus (Adv) on the neural differentiation of bone marrow mesenchymal stem cells (rBMSCs) of rats.Methods The rBMSCs were isolated and cultured by attachment method.The surface marker protein was identified by flow cytometry.The rBMSCs were divided into 4 groups:control group,AdV enhanced green fluorescence protein (Adv-EGFP) + induction group(empty virus group),CT-1 group and induction group.The cells were transfected by Adv in the corresponding multiplicity of infections.Each group was induced by neural induction medium except for control group.The cells morphological changes were observed by microscope and the expressions of Nestin,neuronal nuclei (NeuN) and glial fibrillary acidic protein(GFAP) were detected respectively by cellular immunofluorescence at 5 h,3 d and 7 d after induction.Results After induction treatment,neuron-like cells morphological changes were observed in all the groups except for control group,among which the most obvious change was found in CT-1 group.The positive rate of Nestin was the highest at 5 h after induction.Positive rate of CT-1 group[(86.31 ± 4.27)％] was higher than any other groups,the differences were statistically significant (all P ＜ 0.001);after which its positive rate gradually declined,the positive rate of CT-1 group changed more obviously than other groups,and the differences were statistically significant (all P ＜ 0.001).The difference in Nestin positive rate between the empty virus group and induction group was not statistically significant (all P ＞ 0.05) at various time points.The NeuN and GFAP could be observed in CT-1 group at 5 h after induction.Then the positive rate of NeuN and GFAP increased gradually,and climbed to the highest point [(64.41 ± 3.65)％,(47.14 ± 4.29)％] on 7 d after induction.Positive rate of NeuN and GFAP in CT-1 group at various time points were higher than that of other groups,and the differences were statistically significant (all P ＜0.001).The difference of NeuN and GFAP positive rate between the empty virus group and induction group was not statistically significant (all P ＞ 0.05).Conclusion CT-1 could promote the neural differentiation of rBMSCs.
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Objective: To investigate the protective effect of exogenous cardiotrophi-1 (CT-1) against spinal cord injury and the possible mechanism. Methods: Ninety rats were evenly randomized into 9 groups, namely, before injury (0 h) and 1, 6, 12 hours, 1, 2, 3, 6 and 12 days after injury. RT-PCR was used to examine the expression of CT-1, its receptor gp130, and leukemia inhibitory factor receptor (LIFR) in the injured spinal cord tissues. Rats were also divided into spinal cord injury model group, nerve growth factor (NGF) treatment group and CT-1 treatment group, receiving intradural infusion of normal saline, NGF, and rhCT-1(100 μg·k-1·-1), respectively; the injured tissues were harvested at the 3rd day, one week and 2 weeks after injury for H-E and Nissl staining; and the neuron counts were compared between different groups. Sixty rats were divided into model group and CT-1 treatment group (n=30); the triceps muscle wet weight and total protein weight were compared between the two groups at 1 week, 2 weeks and 4 weeks after spinal cord injury. Results: CT-1 mRNA expression had a transient significant increase after injury (P<0.05), and then it decreased gradually; meanwhile, expression of its receptors increased consequently. The numbers of neurons and Nissl bodies were similar in CT-1-treated group and NGF-treated group, but the numbers of both groups were significantly more than that in the model control group (P<0.05). In addition, the muscle wet weight and protein content in the CT-1-treated group were significantly higher than that in the model control group at 4 weeks and 12 weeks after injury (P<0.05). Conclusion: CT-1 exhibits a protective effect on the survival and function of neurons after spinal cord injury in rats.
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Objective To investigate the effect of hosphocreatine therapy on the plasma cardiotrophin-1(CT-1) and N terminal probrain natriuretic (NT-proBNP) in elderly hypertensive patients with heart failure. Methods A total of 76 hy-pertensive patients with heart failure, aged 65 or over, were randomly divided into treatment group and control group (n=38 for each group). The control group received routine anti-heart failure treatment. The treatment group received conventional therapy plus creatine phosphate sodium for 2 weeks. The plasma levels of CT-1 and NT-proBNP were determined in two groups. The plasma CT-1 level was measured by a double antibody sandwich enzyme-linked immunosorbent assay (ELISA). The plasma level of NT-proBNP was tested by Rui Pu fluorescent dry quantitative analyzer. Results The plasma levels of CT-1 and NT-proBNP were significantly lower after treatment in two groups (P＜0.01). The plasma levels of CT-1 and NT-proBNP were significantly decreased in treatment group than those in control group (P＜0.05). The total effective rate was 89.47%in treatment group, which was significantly higher than that of control group (71.05%, P＜0.05). Symptoms of heart failure improved in one week (21 cases in treatment group/9 cases in control group) and in two weeks (13 cases in treatment group/18 cases in control group). Conclusion The conventional therapy plus creatine phosphate sodium can decrease the plasma CT-1 and NT-proBNP levels in elderly hypertensive patients with heart failure, which improves symptoms of heart failure in a shorter period of time.
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Objective: To investigate the effect of endocannabinoid system on cardiac hypertrophy in experimental rats with chronic intermittent hypoxia and to study the impact of endocannabinoid antagonist, rimonabant in such pathological processing. Methods: A total of 48 male Wistar rats were divided into 6 groups. 4 and 6 weeks of Normal control group, 4 and 6 weeks of Hypoxia group, 4 and 6 weeks of Hypoxia with rimonabant intervention group. n=8 in each group. The rats were sacrificed to measure left ventricular mass index (LVMI), the myocardial cell morphological changes were observed by optical microscope, the expression of cardiac calcium/calmodulin-dependent protein kinase II (CaMKII) and cardiotrophin-1 (CT-1) were detected by immunohistochemistry at 4 and 6 weeks respectively. Results: Compared with 4 and 6 weeks of Normal control group, the LVMI, cardiac hypertrophy condition, CaMKII and CT-1 were increased in 4 and 6 weeks of Hypoxia group, all P Conclusion: The Chronic intermittent hypoxia could induce myocardial hypertrophy via endocannabinoid system disorders, such pathological processing could be reduced by rimonabant intervention.
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Objective: To investigate the effects of rosuvastatin on reactive oxygen species (ROS) production and periostin, cardiotrophin-1 (CT-1) expression, and to explore rosuvastatin on ventricular remodeling in experimental rats after acute myocardial infarction (AMI). Methods: A total of 45 male Wistar rats were randomly divided into 2 group, Sham operation group,n=15 and AMI group,n=30, the AMI model was established by left anterior descending coronary ligation. After 24 hours of AMI, the rats were further divided into 2 groups, AMI + rosuvastatin group, the rats received gastric rosuvastatin 1mg/(kg?d), and AMI group, the rats received gastric normal saline.n=15 in each group and all animals were treated for 6 weeks. The mRNA and protein expressions of CT-1 and periostin were examined by real time RT-PCR and immunohistochemistry, the contents of superoxide anion (O2-·) and hydroxy radical (OH·) were detected by colorimetric method among different groups. Results: Compared with Sham operation group and AMI + suvastatin group, the mRNA and protein expressions of CT-1, periostin, the contents of (O2-·), (OH·) and left heart weight index were increased in AMI group at non-infraction zone,P<005. Compared with Sham operation group, the mRNA and protein expressions of CT-1, periostin, the contents of (O2-·), (OH·) and left heart weight index were increased in AMI + suvastatin group at non-infraction zone,P<005. Compared with AMI group, the mRNA and protein expressions of CT-1 and periostin were decreased in AMI + rosuvastatin group,P<005. Conclusion: Rosuvastatin may improve ventricular remodeling via inhibiting ROS production and CT-1, periostin expression in experimental rats after AMI.
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Objective To explore the changes and significance of plasma cardiotrophin-1 (CT-1) in children with heart failure.Methods Forty children with heart failure (NYHA Ⅱ,n =14;NYHA Ⅲ,n =16;NYHA Ⅳ,n =10)were chosen as observation group,and 20 healthy children without heart failure were taken as healthy control group.Plasma CT-1 was measured by a double antibody sandwich enzyme-linked immunosorbent assay (ELISA).N terminal probrain natriuretic peptide(NT-pro BNP) concentration was tested by Pu Rui fluorescent dry quantitative analyzer.Left ventricular ejection fraction(LVEF) was evaluated by GE Vivid 7 doppler echocardiography and cardiac function assessed by modified ROSS score.Plasma CT-1 level,NT-pro BNP and LVEF were compared between the 2 groups.The correlation of plasma CT-1 level with NT-pro BNP and LVEF were analyzed in patients with different degrees of heart failure.Results Plasma levels of CT-1 and NT-pro BNP were significantly higher in children with heart failure than those in healthy control group (P ＜ 0.01),and with progression of heart failure,the levels of CT-1 and NT-pro B NP progressively increased in heart failure children.Plasma CT-1 level in different NYHA had statistical significance (F =55.5,P ＜0.01).Plasma CT-1 level was positive correlated with NT-pro BNP and modified ROSS score(r =0.787,0.848,all P ＜ 0.01),and negative associated with LVEF (r =-0.66,P ＜ 0.01),respectively,in heart failure children.Conclusions Plasma CT-1 level is significantly elevated in heart failure children.There are good correlation among CT-1,NT-pro BNP and LVEF.Plasma CT-1 is a reliable marker of reflecting the severity of heart failure,combined with NT-pro BNP detection helps to improve the diagnostic accuracy of heart failure in children.
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Background & objectives: In congestive heart failure (CHF), increased concentrations of several cytokines including cardiotrophin-1 (CT-1) and immunactivation are found. This study was performed to evaluate whether CT-1 can induce in vitro cytokines in monocytes and CD4+ T-lymphocytes of healthy volunteers. Methods: The study was performed in vitro to see whether CT-1 can modulate monocyte or CD4+ T-lymphocyte interleukin (IL)-1β, -2, -4, -5, -10, interferon γ (IFNγ), and tumour necrosis factor α (TNFα) expression by flow cytometry following stimulation with CT-1 alone or together with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA)/ionomycine (iono). Results: CT-1 increased the number of TNFα and IL-1β positive monocytes. LPS induced IL-10, TNFα, and IL-1β in monocytes but only IL-2 in CD4+ T-lymphocytes, whereas PMA/iono induced all cytokines besides IL-5 in monocytes and IL-1β in CD4+ T-lymphocytes. In LPS activated monocytes, CT-1 induced a concentration-dependent reduction in the number of TNFα positive monocytes. After LPS activation, CT-1 decreased the number of CD4+ lymphocytes positive for IL-2, IL-4, and IL-5. In addition, following PMA/iono stimulation, CT-1 initiated a concentration-dependent decrease of CD4+ T-lymphocytes positive for TNFα, IL-4, IL-5, and IL-10. Interpretation & conclusions: The present data show that in vitro CT-1 can activate monocytes and modulate cytokine production of activated CD4+ T-lymphocytes. We speculate that CT-1 may at least be partly responsible for immunactivation in CHF.
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Adjuvants, Pharmaceutic , Adult , CD4-Positive T-Lymphocytes/immunology , Cytokines/biosynthesis , Cytokines/immunology , Cytokines/pharmacokinetics , Heart Failure , Humans , Immunosuppressive Agents/pharmacokinetics , Tumor Necrosis Factor-alphaABSTRACT
Objective To study the eorrelation between the plasma cardiotrophin-1(CT-1)level and cardiac function of patients with diabetic cardiopathy.Methods Using the Biotin-StreptAvidin-enzyme-linked immunosorbent assay(BSA-ELISA),the level of plasma CT-1 jn 35 normal controls,40 patients with type 2 diabetes and 60 patients with diabetic cardiopathy was measured.The relation to heart function was observed.Results The difference of plasma CT-1 level in the three groups was significant(all P＜0.05).The level of plasma CT-1 in diabetic cardiopathy group was apparently higher than that of type 2 diabetes group and normal controls(all P＜0.01);The level in type 2 diabetes group was significantly higher than that of normal controls(P＜0.01).The level of plasma CT-1 elevated with the worsening of heart failure(NYHA classification).The level of plasma CT-1 was correlated with EF(r=0.669,P＜0.01);LAD(r=0.528,P＜0.01);PVE(r=0.502,P＜0.01);CK-MB(r=0.312,P＜0.01);TG(r=0.187,P＜0.05);DBP(r=0.158,P＜0.05)o Stepwise regression analysis revealed that EF and LAD were the most significant agents affecting the plasma CT-1.Conclusion The plasma CT-1 level could reflect the state of cardiac function of diabetic cardiopathy patient,it could help to diagnose diabetic cardiopathy earlier.
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Objective To study the effect of Cardiotrophin-1 (CT-1) on cardiocyte hypoxia-reoxygenation injury,and to investigate the signaling pathways involved in the protective effect. Method This study was carried out in Key Lab of Molecular Medicine in Jiangxi Province. Cardiomyocytes from the hearts of 2-day-old Sprague-Dawley neonatal rats were prepared by a modified method. Five groups were included in the study. Group (ⅰ): control, Group (ⅱ): hypoxia/reoxygeuation, Group (ⅲ): hypoxia / reoxygenation + CT-1, Group (iv) : CT- 1 + hypoxia/ reoxygenation + LY294002 (PIK3/Akt inhibitor), Group (ⅴ): CT-1 + hypoxia / reoxygenation +DMSO. The concentration of CT-1 was 10 ng/mL. Myocytes survival rote was evaluated by MTS method, apopto-sis, mitochondrial permeability transition pore (△ψm) and reactive oxygen species(ROS) were detected by flow cy-tometer, phosphorylased GSK-3β and PI3K protein by western blotting. Analysis of variance and q test as statistical methods was used to analyze the data. Results Cardiomyocyte apoptosis and ROS increased markedly after hy-poxia/reoxygenation,but cardiomyocyte survival rate and the level of △ψm [(40.55±4.25) vs. (86.28±7.15), P < 0.01]decreased significantly. With CT-1 intervention, cardiomyocyte survival rate increased markedly (87%),apoptosis and ROS reduced significantly. The level of △ψm increased, the level of phosphorylased GSK-3β and phosphorylased PI3K protein obviously increased. The effect of CT-1 was inhibited by LY294002, but no significant effect was observed on ceils survival in DMSO group, which confirmed that LY294002 specifically in-volved blocking the protective effect of CT-1. Conclusions CT-1 can protect cardiac cells against hypoxia- reoxy-genation injury, these effects are dependent upon its ability to activate the PI3K/GSK-3β pathway.
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AIM: To observe the change of subunit of NADPH oxidation enzyme complex nox - 1 protein in cardiocyte hypoxia - reoxygenation injury and the role of cardiotrophin -1.METHODS: Cardiomyocytes from the hearts of 1 -3 d old neonatal rats were prepared by a modified method. Five groups were included in the study: control; hypoxia/ reoxygenation; hypoxia/reoxygenation + CT - 1; CT - 1 + hypoxia/reoxygenation + LY294002 (PIK3/Akt inhibitor) ; CT -1 + hypoxia/reoxygenation + PD98059 (ERK inhibitor) ; CT - 1 + hypoxia/reoxygenation + DMSO. The concentration of CT -1 was 10 μg/L. The survival rate of myocytes was evaluated by MTS method. Apoptosis, mitochondrial permeability transition pore ( △ψm) and reactive oxygen species ( ROS) were detected by flow cytometry. Nox - 1 protein was determined by Western blotting. RESULTS: Apoptosis of cardiomyocytes and the level of ROS (19.7% ±1.4% vs 2.1% ± 0.5% , 14.07% ± 1.25% vs 3.54% ± 0.86% , P < 0.05 ) increased markedly after hypoxia/reoxygenation, but cardio-myocyte survival rate and the level of△ψm (40.55% ±4.25% vs 86.28% ±7.15% , P <0.01) decreased significantly. The expression of nox - 1 protein was upregulated markedly. With CT - 1 intervention, cardiomyocyte survival rate increased markedly, apoptosis, both ROS and expression of nox - 1 protein reduced significantly. The level of△ψm increased obviously. The effect of CT - 1 was inhibited by LY294002.No significant effect was observed on cells survival in DMSO group, which confirmed that LY294002 was specifically involved in blocking the protective effect of CT - 1.CONCLUSION : The expression of subunit of NADPH oxidation enzyme complex nox - 1 protein is upregulated markedly in cardiocyte hypoxia - reoxygenation injury.CT - 1 protects cardiac cells against hypoxia - reoxygenation injury by downregulating the expression of nox -1 protein to decrease the level of ROS.
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BACKGROUND AND OBJECTIVES: Adriamycin (doxorubicin, ADR) is a highly effective anti-neoplastic drug, but its clinical use is limited by its adverse side effects on the heart. Cardiotrophin (CT-1), a potent cardiac survival factor, is capable of inhibiting apoptosis in cardiac myocytes. The aim of this study was to investigate the cyto-protective effects of CT-1 against ADR-induced apoptosis in vitro. MATERIALS AND METHODS: We determined a reasonable ADR concentration for inducing cell death by utilizing a cell survival test performed in a dose-dependent manner. To determine the requirements for apoptosis in ADR-treated cardiac myocytes (H9c2 cells), we examined the effect of CT-1 on survival and apoptotic changes using a cell counting kit (CCK), RT-PCR, and Western blotting. RESULTS: In analyzing cell survival as determined by CCK, ADR-induced cell death was found to occur in a dose-dependent manner (50% death at 24 hours after 2 micrometer of ADR), and ADR was shown to decrease procaspase-3. On RT-PCR, expression of Bax-alpha mRNA increased and Bcl-2 decreased during the 24 hours after ADR treatment. Consequently, the ratio of Bax-alpha/Bcl-2 mRNA peaked at 24 hours after ADR treatment. In contrast, CT-1 effectively attenuated the ADR-induced cell death in a dose-dependent manner. The changes in Bax-alpha and Bcl-2 mRNA expression after ADR treatment were reversed by CT-1 (1 ng/mL) treatment. The protein levels of procaspase-3 decreased after ADR treatment, an effect which was reversed by CT-1 treatment. Akt phosphorylation was also increased by CT-1, demonstrating that CT-1 inhibited apoptosis induced by ADR. CONCLUSION: These data demonstrated that ADR-induced apoptosis of cardiomyocytes can be prevented by CT-1; therefore, it may be possible to use CT-1 as a cardioprotective agent during ADR chemotherapy in patients with cancer.
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Humans , Apoptosis , Caspase 3 , Cell Count , Cell Death , Cell Survival , Cytoprotection , Doxorubicin , Heart , Myocytes, Cardiac , Phosphorylation , RNA, MessengerABSTRACT
Objective To observe biological effect of cardiotrophin-1(Adv-CT1)gene transfection mediated by adnovims on traumatic brain iniuries(TBI)in-vivo and discuss the role and mechanism of Adv-CT1 on TBI. Metheds A rat TBI model was established bv Allen method.After Adv-CT1 was transfefred into the iniured brain by adnovims,the effect of CT-1 on apoptosis and survival of neurons after TBI was determined by means of Nissl staining,TUNEL and flow cytometry apoptosis assay. Resuits Apoptotic cells were increased but the survived cells decreased in the injured cortical brain and hippocampus from 12 hours to 14 days after TBI in the control group.As compared with control group,Adv-CT1 treatment reversed this situation to some degrees. Conclusion CT-1 has neuropmtective effect on neurons after TBI by reducing apoptosis of neurons.
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Objective Cardiac muscle cells play a critical role in maintaining normal function of the heart.Cardiotrophin-1(CT-1),a potent cardiac survival factor,is capable of inhibiting apoptosis or promoting survival in cardiomyocytes.To elucidate the mechanism of CT-1 promoting cardiac myocyte survival in cultured neonatal rat cardiomyocytes.To explore the potential signaling pathway that might be responsible for this effect.Methods We examined the cardiac myocyte survival effect of CT-1 in cultured neonatal rat cardiomyocytes.The cardiomyocytes were stained [3-(4,5-dimethyl-thiaziazol-2-yl)-2-5-diphenyltetrazolium bromide,MTT] and the counted.Results The survival rate of cardiac myocytes was increased by CT-1 in a dose-dependent manner(10-10～10-7 mol/L) and in a time-dependent manner(1～4 d,10-8 mol/L) in cultured neonatal rat cardiomyocytes.Pretreatment of PD098059(5?10-5mol/L),a MAPK blocker,decreased significantly survival rate of cardiac myocytes by promoted CT-1.The phorbol 12-myristate 13-acetate(PMA)(10-5mol/L),a PKC activator,increased significantly this effect of CT-1,but inhibited significantly by MAPK blocker PD098059.Conclusion CT-1 is a potent factor of promoting cardiac myocyte survival,and increase significantly survival rate of cardiac myocytes in a dose-dependentand a time-dependent manner in cultured neonatal rat cardiomyocytes.The MAPK signaling pathway mediates CT-1 induced cardiac myocyte survival.PKC signaling molecule may be a upstream signaling transduction pathway which cascades of MAPK in CT-1 induced cardiac myocyte survival.
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Objective To explore the expression of cardiotrophin-1(CT-1) in myocardium and peripheral blood plasma of neonatal rat with asphyxia and the regulative effect of neuregulin-1(NRG-1).Methods Ninety seven-day-old neonatal rats were randomly divided into 3 groups:asphyxia group (n=40),normal control group (n=10)and NRG-1 pretreatment group (n=40).The model of neonatal rat with asphyxia was prepared by the way of ligation of carotid combined with low supply of oxygen.NRG-1(1 mg/kg) was given to NRG-1 pretreatment group by intraperitoneal injection 30 min before asphyxia.The separated plasma of peripheral blood and myocardium antetheca of aortic ventricle of heart were taken at the time point of 6,12,24 and 48 h.The expression of CT-1 in peripheral blood plasma was detected by enzyme linked immunoadsorbent assay,and that of myocardium was determined by Western blot.Results The expressions of CT-1 protein in peripheral blood plasma of asphyxia group were significantly higher than those of normal control group at each time point,and reached the peak at 24 h(Pa
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Objective To investigate the changes of GP130 expression in rats with pressure overload-induced cardiac hypertrophy, and the effect of Benazepril on GP130 expression and the concerned cardiac hypertrophy. Methods Two weeks after the Wistar rat model of pressure overload was established by constriction of abdominal aorta, the survived rats were randomly divided into hypertrophy group (LVH, n=7) and Benazepril intervention group (Ben, n=7, 1 mg?kg -1 ?d -1 Benazepril orally for 3 weeks). A sham-operation group (Sham, n=7) was set up as control. Blood pressure and left ventricular mass index (LVMI) were investigated at 3th week after model establishment. AngⅡ level in myocardium was measured by radioimmunoassay. The protein level of GP130 in cardiomyocytes was determined by immunohistochemistry. Results As compared with the Sham group, blood pressure and LVMI increased significantly (P
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Objective To investigate the changes of cardiotrophin-1(CT-1) expression in rats with pressure overload-induced cardiac hypertrophy,and the effects of benazepril on this expression and the concerned cardiac hypertrophy.Methods The model of pressure overload was established by constriction of abdominal aorta and divided randomly into hypertrophied group(LVH,n=7) and benazepril intervention group(Ben,n=7,benazepril 1mg?kg~(-1)?d~(-1) orally)2 weeks later.A sham-operation group(Sham,n=7) served as control.Blood pressure and left ventricular mass index(LVMI) were investigated after 3 weeks' treatment.AngⅡ level in myocardium was measured by radioimmunoassay.The mRNA level of CT-1 was examined by RT-PCR.Results Compared with the sham group, blood pressure and LVMI in LVH group were increased significantly(P