RESUMEN
BACKGROUND: Human amniotic epithelial cells (hAECs) are seed cells used to treat acute myocardial infarction (AMI), but their mechanism remains unclear. METHODS: We cultured hAECs and extracted exosomes from culture supernatants. Next, we established a stable AMI model in rats and treated them with hAECs, exosomes, or PBS. We assess cardiac function after treatment by echocardiography. Additionally, heart tissues were collected and analyzed by Masson's trichrome staining. We conducted the tube formation and apoptosis assays to explore the potential mechanisms. RESULTS: Cardiac function was improved, and tissue fibrosis was decreased following implantation of hAECs and their exosomes. Echocardiography showed that the EF and FS were lower in the control group than in the hAEC and exosome groups, and that the LVEDD and LVESD were higher in the control group (P<0.05). Masson's trichrome staining showed that the fibrotic area was larger in the control group. Tube formation was more efficient in the hAEC and exosome groups (P<0.0001). Additionally, the apoptosis rates of myocardial cells in the hAEC and exosome groups were significantly decreased (P<0.0001). CONCLUSIONS: hAECs and their exosomes improved the cardiac function of rats after AMI by promoting angiogenesis and reducing the apoptosis of cardiac myocytes.
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Amnios/citología , Células Epiteliales/metabolismo , Células Epiteliales/trasplante , Exosomas/trasplante , Corazón/fisiopatología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Animales , Apoptosis , Células Cultivadas , Modelos Animales de Enfermedad , Electrocardiografía , Exosomas/metabolismo , Exosomas/ultraestructura , Fibrosis , Humanos , Masculino , Infarto del Miocardio/diagnóstico por imagen , Miocitos Cardíacos , Ratas Sprague-DawleyRESUMEN
The association between body mass index (BMI) and mortality of patients with percutaneous coronary intervention (PCI) is still controversial. We hope to explore whether the 'obesity paradox' really exists through this dose-response meta-analysis. PubMed, Embase and Cochrane databases were systematically searched for eligible studies up to April 2020. The random-effects restricted cubic spline models were used to evaluate the potential non-linear relationship between BMI and all-cause mortality of patients undergoing PCI. Fifteen studies were identified and included total 138 592 participants. The pooled hazard ratio of all-cause mortality was 0.60 (95% confidence interval: 0.45-0.82) when compared the highest category (mean = 33.32 kg m-2 ) of BMI with the lowest category (mean = 18.89 kg m-2 ). A non-linear U-shaped dose-response curve between BMI and the risk of all-cause mortality was found, with higher mortality rate at BMI lower than 27 kg m-2 and higher than 32 kg m-2 . The 'obesity paradox' does exist after PCI. The association between BMI and the risk of all-cause mortality for patients undergoing PCI is U shaped, with a nadir of risk at a BMI of 27 to 32 kg m-2 and the highest risk at patients with underweight. The relationship between other prognostic indicators and BMI is worthy of further research.
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Índice de Masa Corporal , Mortalidad , Obesidad , Intervención Coronaria Percutánea , Humanos , Pronóstico , Factores de Riesgo , DelgadezRESUMEN
Trials studying iron administration in patients with chronic heart failure (CHF) and iron deficiency (ID) have sprung up these years but the results remain inconsistent. The aim of this meta-analysis was to comprehensively evaluate the efficacy and safety of iron therapy in patients with CHF and ID. A literature search was conducted across PubMed, Embase, Cochrane Library, OVID and Web of Science up to 31 July 2019 to search for randomised controlled trials (RCT) comparing iron therapy with placebo in CHF with ID, regardless of presence of anaemia. Published studies reporting data of any of the following outcomes were included: all-cause death, cardiovascular hospitalisation, adverse events, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), N-terminal pro b-type natriuretic peptide, peak oxygen consumption, 6 min walking test (6MWT) distance and quality of life (QoL) parameters. 15 RCTs with a total of 1627 patients (911 in iron therapy and 716 in control) were included. Iron therapy was demonstrated to reduce the risk of cardiovascular hospitalisation (OR 0.35, 95% CI 0.12 to 0.99, p=0.049), but was ineffective in reducing all-cause death (OR 0.59, 95% CI 0.33 to 1.06, p=0.078) or cardiovascular death (OR 0.80, 95% CI 0.39 to 1.63, p=0.540). Iron therapy resulted in a reduction in NYHA class (mean difference (MD) -0.73, 95% CI -0.99 to -0.47, p<0.001), an increase in LVEF (MD +4.35, 95% CI 0.69 to 8.00, p=0.020), 6MWT distance (MD +35.44, 95% CI 11.55 to 59.33, p=0.004) and an improvement in QoL: EQ-5D score (MD +4.07, 95% CI 0.84 to 7.31, p=0.014); Minnesota Living With Heart Failure Questionnaire score (MD -19.47, 95% CI -23.36 to -15.59, p<0.001) and Patients Global Assessment (PGA) scale (MD 0.71, 95% CI 0.32 to 1.10, p<0.001). There was no significant difference in adverse events or serious adverse events between iron treatment group and control group. Iron therapy reduces cardiovascular hospitalisation in patients with CHF with ID, and additionally improves cardiac function, exercise capacity and QoL in patients with CHF with ID and anaemia, without an increase of adverse events.
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Anemia Ferropénica , Insuficiencia Cardíaca , Hierro , Anemia Ferropénica/complicaciones , Anemia Ferropénica/tratamiento farmacológico , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Hematínicos/farmacología , Humanos , Hierro/farmacología , Deficiencias de Hierro , Resultado del TratamientoRESUMEN
A number of studies have showed the relationship between R353Q (rs6046) polymorphism in factor VII gene and coronary heart disease (CHD). However, the results remain controversial due to the limitations of the research objects and small sample size of individual study. We conducted this meta-analysis to validate the association between R353Q (rs6046) polymorphism and the risk of CHD.The relevant data was collected up to March 25, 2019 from PubMed, Web of Science, CNKI, and Wanfang databases. We examined all eligible studies using the Newcastle-Ottawa Quality Assessment Scale (NOS). The odds ratio (OR) and its corresponding 95% confidence interval (CI) were adopted to evaluate the relationship between the R353Q (rs6046) polymorphism and CHD. Stata version 14.0 (Stata Corporation, USA) was used in all statistical tests.There were at least 28 eligible studies, including 14626 cases and 17994 controls, included in our meta-analysis. R353Q (rs6046) polymorphism was associated with the reduced risk of CHD in four genetic models: allele model (Q versus R: OR = 0.79, 95% CI: 0.69 to 0.90, P < 0.001, I2 = 56.4%), homozygote (co-dominant) model (QQ versus RR: OR = 0.72, 95% CI = 0.58 to 0.92, P = 0.004, I2 = 5.8%), heterozygote (co-dominant) model (RQ versus RR: OR = 0.71, 95% CI = 0.58 to 0.86, P = 0.001, I2 = 75.4%), and dominant model (RQ+QQ versus RR: OR = 0.74, 95% CI = 0.63 to 0.865, P < 0.001, I2 = 64.1%) excluding recessive model (QQ versus RR+RQ: OR = 0.86, 95% CI = 0.57 to 1.28, P = 0.447, I2 = 51.6%).The results of the current meta-analysis suggested that R353Q (rs6046) polymorphism was associated with the reduced risk of CHD, especially in Asians.
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Enfermedad Coronaria/genética , Factor VII/genética , Humanos , Polimorfismo de Nucleótido Simple , Factores ProtectoresRESUMEN
Left ventricular diastolic dysfunction (LVDD) remains challenging to be assessed by echocardiography. We sought to explore the relationship between left atrial strain and left ventricular (LV) diastolic function in patients with normal left ventricular ejection fraction (LVEF) by invasive left-heart catheterization. 55 consecutive individuals with LVEF > 50% underwent LV catheterization. Standard transthoracic echocardiography was performed during 12 h before or after the procedure. Left atrial (LA) strain were obtained by speckle tracking echocardiography. When LVEF ≥ 50%, the group with elevated left ventricular end-diastolic pressure (LVEDP) (n = 35) showed decreased left atrial reservoir strain (LASr) (35.2 ± 7.7% vs 21.3 ± 7.2%, p < 0.001), left atrial conduit strain (LASct) (17.6 ± 6.3% vs 11.9 ± 4.1%, p < 0.001), left atrial contraction strain (LAScd) (16.6 ± 7.2% vs 9.5 ± 5.0%, p < 0.001) and increased E/e' ration(8.9 ± 2.6 vs 10.1 ± 3.5, p = 0.17). LVEDP negatively correlated with LASr (R = 0.662, p < 0.001), LASct (R = 0.575, p < 0.001) and LAScd (R = 0.456, p < 0.001), but not with E/e'. LASr, LASct and LAScd were all independent predictors of elevated LVEDP (p < 0.05), with a higher C-statistic for the model including LASr (0.95, 0.86 and 0.93 respectively). The area under the curve (AUC) for LASr is 0.914 (cutoff value is 26.7%, sensitivity is 90%, specificity is 82.9%). In patients with normal LV ejection fraction, left atrial strain presented good correlation with LVEDP, and LASr was superior to LASct and LAScd to predict LVEDP. LA strain demonstrated better agreement with the invasive reference than E/e'.
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Función del Atrio Izquierdo , Cateterismo Cardíaco , Ecocardiografía Doppler , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Función Ventricular Izquierda , Presión Ventricular , Anciano , Cateterismo Cardíaco/instrumentación , Catéteres Cardíacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Transductores de Presión , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Aldehyde dehydrogenase-2 (ALDH2) rs671 G>A polymorphism can influence the activity of ALDH2 and may be associated with the risk of essential hypertension (EH). Although many previous studies have explored such a relationship, the conclusion is still controversial.The PubMed, Embase, and China National Knowledge Infrastructure databases were searched on the ALDH2 gene and EH. We used the Newcastle-Ottawa Scale to evaluate the quality of the study. Then we calculated the strength of relationship between ALDH2 rs671 mutation and EH by utilizing odds ratios and 95% confidence intervals. Besides, subgroup analysis and sensitivity analysis were performed and the publication bias was assessed.There were 12 studies containing 8153 cases and 10,162 controls. Our meta-analysis showed significant association between ALDH2 rs671 polymorphism and EH in four genetic models (the allele model, the homozygote model, the heterozygote model, and the dominant model), whereas it did not indicate this connection in the recessive model. However, a trend of decreased risk still could be seen. Furthermore, we also found an obvious association between rs671 mutation and the risk of EH in the male group than in the female group in all five genetic models.We concluded that ALDH2 rs671 G>A polymorphism may decrease the risk of EH. Furthermore, susceptibility to EH reduced in males but not in females. As a variant in ALDH2, rs671 G>A could be an attractive candidate for genetic therapy of EH. In addition, more case-control studies should be conducted to strengthen our conclusion and evaluate the gene-gene and gene-environment interactions between the ALDH2 gene and EH.
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Aldehído Deshidrogenasa Mitocondrial/genética , Hipertensión Esencial/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotension system, however, the correlation between ACE2 and prognosis in UCEC (Uterine Corpus Endometrial Carcinoma) and KIRP (Kidney Renal Papillary Cell Carcinoma) is not clear. We analyzed the expression levels of ACE2 in the Oncomine and TIMER databases, the correlation between ACE2 and overall survival in the PrognoScan, GEPIA and Kaplan-Meier plotter databases. The correlation between ACE2 and immune infiltration level and the type markers of immune cells was investigated in TIMER database. A prognosis analysis based on the expression levels of ACE2 was further performed in related immune cells subgroup. The ACE2 promoter methylation profile was tested in the UALCAN database. In addition, we used GSE30589 and GSE52920 databases to elucidate the changes of ACE2 expression in vivo and in vitro after SARS-CoV infection. ACE2 was elevated in UCEC and KIRP, and high ACE2 had a favorable prognosis. The expression of ACE2 was positively correlated with the level of immune infiltration of macrophage in KIRP, B cell, CD4+T cell, neutrophil and dendritic cell immune infiltration levels in UCEC. ACE2 was significantly positively correlated with the type markers of B cells and neutrophils, macrophages in UCEC, while ACE2 in KIRP was positively correlated with the type markers of macrophages. High ACE2 expression level had a favorable prognosis in different enriched immune cells subgroups in UCEC and KIRP. And the promoter methylation levels of ACE2 in UCEC and KIRP were significantly reduced. What's more, we found that the expression of ACE2 decreased in vivo and in vitro after SARS-CoV infection. In conclusion, ACE2 expression increased significantly in UCEC and KIRP, elevated ACE2 was positively correlated with immune infiltration and prognosis. Moreover, tumor tissues may be more susceptible to SARS-CoV-2 infection in COVID-19 patients with UCEC and KIRP, which may worsen the prognosis.
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Betacoronavirus , Carcinoma de Células Renales , Infecciones por Coronavirus , Neoplasias Endometriales , Inmunidad Celular , Neoplasias Renales , Pandemias , Peptidil-Dipeptidasa A/biosíntesis , Neumonía Viral , Enzima Convertidora de Angiotensina 2 , Biomarcadores de Tumor , COVID-19 , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Pronóstico , SARS-CoV-2RESUMEN
BACKGROUND: There is currently no classification for acute myocardial infarction (AMI) according to left ventricular ejection fraction (LVEF). We aimed to perform a retrospective analysis of patients undergoing emergency percutaneous coronary intervention (PCI), comparing the clinical characteristics, in-hospital acute heart failure and all-cause death events of AMI patients with mid-range ejection fraction (mrEF), preserved ejection fraction (pEF) and reduced ejection fraction (rEF). MATERIAL AND METHODS: Totally 1270 patients were stratified according to their LVEF immediately after emergency PCI into pEF group (LVEF 50% or higher), mrEF group (LVEF 40%-49%) and rEF group (LVEF <40%). Kaplan-Meier curves and log rank tests were used to assess the effects of mrEF, rEF and pEF on the occurrence of acute heart failure and all-cause death during hospitalisation. The Cox proportional hazards model was used for multivariate correction. RESULTS: Compared with mrEF, rEF was an independent risk factor for acute heart failure events during hospitalisation (HR 5.01, 95% CI 3.53 to 7.11, p<0.001), and it was also an independent risk factor for all-cause mortality during hospitalisation (HR 7.05, 95% CI 4.12 to 12.1, p<0.001); Compared with mrEF, pEF was an independent protective factor for acute heart failure during hospitalisation (HR 0.49, 95% CI 0.30 to 0.82, p=0.01), and it was also an independent protective factor for all-cause death during hospitalisation (HR 0.33, 95% CI 0.11 to 0.96, p=0.04). CONCLUSIONS: mrEF patients with AMI undergoing emergency PCI share many similarities with pEF patients in terms of clinical features, but the prognosis is significantly worse than that of pEF patients, suggesting that we need to pay attention to the management of mrEF patients with AMI.
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Causas de Muerte , Mortalidad Hospitalaria , Infarto del Miocardio/terapia , Intervención Coronaria Percutánea/métodos , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Anciano , China , Estudios de Cohortes , Angiografía Coronaria/métodos , Urgencias Médicas , Femenino , Hospitales Universitarios , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea/mortalidad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Disfunción Ventricular Izquierda/mortalidad , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
The increased proliferation and migration of vascular smooth muscle cells (VSMCs) are key events in the development of artery restenosis following percutaneous coronary intervention. Digoxin has long been used in the treatment of heart failure and has been shown to inhibit the proliferation of cancer cells through multiple pathways. However, the potential role of digoxin in the regulation of VSMC proliferation and migration and its effectiveness in the treatment of cardiovascular diseases, such as restenosis, remains unexplored. In the present study, we demonstrate that digoxin-induced growth inhibition is associated with the downregulation of CDK activation and the restoration of p27Kip1 levels in platelet-derived growth factor (PDGF)-stimulated VSMCs. In addition, we found that digoxin restored the PDGFBB-induced inhibition of integrin linked kinase (ILK) expression and prevented the PDGFBB-induced activation of glycogen synthase kinase (GSK)-3ß. Furthermore, digoxin inhibited adhesion molecule and extracellular matrix relative protein expression. Finally, we found that digoxin significantly inhibited neointima formation, accompanied by a decrease in cell proliferation following vascular injury in rats. These effects of digoxin were shown to be mediated, at least in part, through an increase in ILK/Akt signaling and a decrease in GSK-3ß signaling in PDGFBB-stimulated VSMCs. In conclusion, our data demonstrate that digoxin exerts an inhibitory effect on the PDGFBB-induced proliferation, migration and phenotypic modulation of VSMCs, and prevents neointima formation in rats. These observations indicate the potential therapeutic application of digoxin in the treatment of cardiovascular diseases, such as restenosis.
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Traumatismos de las Arterias Carótidas/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Digoxina/farmacología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Neointima/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-sis/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Becaplermina , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/patología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Neointima/patología , RatasRESUMEN
BACKGROUND: Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODSâANDâRESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05). CONCLUSIONS: In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.
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Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/análogos & derivados , Amoníaco , Animales , Glucemia/análisis , Capilares/patología , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Colágeno/biosíntesis , Colágeno/genética , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/fisiopatología , Angiopatías Diabéticas/diagnóstico por imagen , Angiopatías Diabéticas/fisiopatología , Evaluación Preclínica de Medicamentos , Clorhidrato de Fingolimod , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/biosíntesis , Interleucina-6/genética , Lisofosfolípidos , Masculino , Microcirculación/efectos de los fármacos , Miocardio/química , Miocardio/patología , Radioisótopos de Nitrógeno , Tomografía de Emisión de Positrones/métodos , Glicoles de Propileno/farmacología , Ratas , Ratas Sprague-Dawley , Esfingosina/farmacología , Esfingosina/uso terapéutico , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/genéticaRESUMEN
OBJECTIVE: To explore the effects of digoxin on hypoxia-induced pulmonary artery hypertension (PAH) and the possible mechanisms. METHODS: A total of 48 Sprague-Dawley rats were randomly divided into 4 groups: normoxia control, normoxia+digoxin, hypoxia control and hypoxia+digoxin. The animals were exposed to chronic intermittent hypoxia (PO2: (10.5 ± 0.5) %, 8:00-16:00) or room air for 21 days.Each rat received a daily intraperitoneal injection of either digoxin (1.0 mg × kg⻹ × d⻹) or an equal volume of vehicle, starting at the first day of hypoxia or normoxia. At Day 21, mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (RV/(LV+S)) and index of wall thickness of small pulmonary artery (WT% and WA%) among groups were compared. And in vitro the changes of pulmonary artery smooth muscle cells (PASMCs) proliferation were determined by methyl thiazolyl tetrazolium (MTT) assay. Migration assay was performed with a Transwell chamber.Real-time quantitative polymerase chain reaction (PCR) was performed to quantify the mRNA levels of smooth muscle cell phenotype markers such as smooth muscle-α-actin, calponin and smooth muscle 22α under normoxic or hypoxic conditions in the absence or presence of digoxin. And the protein expressions of matrix metalloproteinase (MMPs) were determined by Western blot. RESULTS: Digoxin treatment significantly lowered mPAP, reduced WT% and WA% and right ventricular hypertrophy compared with those of the hypoxic group (mPAP: (27.3 ± 2.7) vs (38.5 ± 2.3) mmHg (1 mmHg = 0.133 kPa); RV/(LV+S): (30.9 ± 3.3)% vs (42.8 ± 2.6)%, WT%: (21.7 ± 3.6)% vs (39.3 ± 2.0)%; WA%: (56.3 ± 4.7)% vs (79.5 ± 5.7)%, all P < 0.05). And in vitro, digoxin restored the hypoxia-induced inhibition of the expression of smooth muscle cell phenotype markers and prevented the hypoxia-induced activation of MMPs in PASMCs. CONCLUSION: Early digoxin therapy reduces pulmonary artery remodeling in hypoxia-induced PAH rat model and this effect is probably correlated with the inhibitions of proliferation, migration, phenotype switching and expression of MMPs induced by hypoxia in PASMCs.
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Digoxina/farmacología , Hipertensión Pulmonar/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Animales , Proliferación Celular , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipoxia , Metaloproteinasas de la Matriz/metabolismo , Células Musculares/efectos de los fármacos , Músculo Liso Vascular/citología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Stem cells transplanted to the ischemic myocardium usually encounter massive cell death within a few days after transplantation, and hypoxic preconditioning (HPC) is currently used as a strategy to prepare stem cells for increased survival and engraftment in the heart. The purpose of this study is to determine whether Pim-1 kinase mediates any beneficial effects of HPC for human cardiac progenitor cells (CPCs). METHODS AND RESULTS: Human CPCs were isolated from an adult heart auricle and were purified by magnetic-activated cell sorting using c-kit magnetic beads; they were hypoxic preconditioned for 6h. Both Pim-1 and p-Akt were determined. CPCs were assigned to one of the following groups: (1) control (without HPC); (2) HPC; or (3) HPC+I (Pim-1 inhibitor). HPC can promote the survival of CPCs. HPC enhances the expression of Pim-1 kinase in a time-dependent manner, which causes a reduction of proapoptotic elements (cytochrome c and cleaved caspase-3) and the preservation/modulation of important components of the mitochondria (Bcl-2, Bcl-XL and p-Bad), and attenuates mitochondrial damages. All of these protective effects were blocked by a Pim-1 inhibitor. CONCLUSIONS: Pim-1 plays a pivotal role in the protective effect of HPC for CPCs, and the promotion of the expression of Pim-1 in CPCs can as serve part of molecular therapeutic interventional strategies in the treatment of cardiomyopathy damage by blunting CPC death.
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Precondicionamiento Isquémico Miocárdico , Mitocondrias Cardíacas/metabolismo , Proteínas Musculares/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Células Madre/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Masculino , Mitocondrias Cardíacas/patología , Proteínas Musculares/antagonistas & inhibidores , Miocitos Cardíacos/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Células Madre/patologíaRESUMEN
Recent studies have found that cardiac stem cells (CSCs) are present in the adult heart. CSCs play an important role in maintaining the balance of the number of myocardial cells. The purpose of this study was to examine characteristics of human CSCs and their correlation with clinical characteristics of patients. We collected heart auricles of 105 patients (age range, 1-78 years; mean, 55.6 ± 17.0 years) undergoing cardiac surgery to obtain CSCs. We assayed the percentage of c-kit positive (c-kit(+)) CSCs with flow cytometry. Plasma N(É)-(carboxymethyl)lysine (CML) concentrations were measured by enzyme-linked immunosorbent assay. The percentage of c-kit(+) CSCs was 4.96 ± 3.12% (0.98-17.17%), and this was significantly negatively correlated with age, the presence of diabetes mellitus (DM) and coronary heart disease (CHD) (r values were -0.797 [P < 0.01], -0.500 [P < 0.01] and -0.250 [P = 0.011], respectively). The percentage of c-kit(+) CSCs was significantly negatively correlated with CML concentrations (r = -0.859, P < 0.01). The percentage of c-kit(+) CSCs decreases with ageing and is further decreased in patients with DM and/or CHD. Furthermore, plasma CML concentrations may have potential as an indicator of the number of c-kit(+) CSCs.
Asunto(s)
Enfermedad de la Arteria Coronaria/patología , Diabetes Mellitus/patología , Miocardio/citología , Células Madre/fisiología , Adolescente , Adulto , Factores de Edad , Anciano , Células Cultivadas , Niño , Preescolar , Enfermedad de la Arteria Coronaria/cirugía , Complicaciones de la Diabetes/patología , Complicaciones de la Diabetes/cirugía , Citometría de Flujo , Humanos , Lactante , Lisina/análogos & derivados , Lisina/sangre , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Células Madre/patología , Adulto JovenRESUMEN
Heart disease is one of the most important causes of death in developed countries. N(ε)-carboxymethyllysine (CML) is a major advanced glycation end product formed by combined reactions of non-enzymatic glycation and oxidation (glycoxidation), and it represents a general marker of oxidative stress. CML has been suggested to be involved in the pathogenesis of heart disease. Plasma CML is elevated in aging, atherosclerosis and/or diabetes. In this study, we measured cardiac CML levels to elucidate its role in the pathogenesis of heart disease. Cardiac tissues were collected from 105 patients (55.6 ± 17.0 years old: age range, 1-78 years) undergoing cardiac surgery. The diseases comprised coronary heart disease (CHD), CHD associated with diabetes mellitus (DM), valvular heart disease and congenital heart disease. The concentration of CML in cardiac tissues of each group was 4.31 ± 0.66, 5.29 ± 0.59, 2.74 ± 1.05 and 1.75 ± 1.16 µg/g, respectively. ELISA was used for measuring cardiac and plasma CML concentrations. Multiple linear regression analysis showed a significant positive correlation of CML concentrations with age (r = 0.803, p < 0.001), DM (r = 0.567, p < 0.001) and CHD (r = 0.523 p < 0.001). R(2) was 0.872 (p < 0.001); the three independent variables could explain 87.2% variation of CML concentrations. Cardiac CML concentrations exhibited a significant positive correlation with plasma CML (r = 0.983, p < 0.001). Our data indicate that cardiac CML concentrations increase with age, DM and/or CHD, and exhibit a positive correlation with plasma CML concentrations.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus/metabolismo , Lisina/análogos & derivados , Miocardio/metabolismo , Adolescente , Adulto , Anciano , Envejecimiento/sangre , Niño , Preescolar , Enfermedad de la Arteria Coronaria/sangre , Diabetes Mellitus/sangre , Femenino , Glicosilación , Humanos , Lactante , Lisina/sangre , Lisina/metabolismo , Masculino , Persona de Mediana Edad , Miocardio/patología , Oxidación-Reducción , Fumar/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Loss of cardiomyocytes after myocardial infarction (MI) causes heart failure. In this study, we investigate whether the in situ cardiomyocytes can re-enter the cell cycle and to what extent cell division of cardiomyocytes occurs after acute MI (AMI) in rats. METHODS: Sprague Dawley (SD) rats were used in this study; the left anterior descending coronary artery was ligated. At time points (3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks) after the operation, five rats were euthanized, respectively. An additional five sham-operated rats serves as a control group and were euthanized at 3 days post-operation. The expressions of cyclin A2, Ki-67, phospho-histone H3 (H3P), and Aurora B in myocardial tissues were detected by Western blot and immunofluorescence. RESULTS: The expression levels of cyclin A2 were significantly higher in all groups with AMI except the 4-week group than those found in the sham-operated group (P < 0.01). The percentage of Ki-67-positive nuclei in the border zones was significantly higher than the percentage in the distant normal myocardium (P < 0.01). CONCLUSIONS: our results demonstrate that cardiomyocytes re-enter the cell cycle after AMI and that cyclin A2 is a reliable marker for the detection of cell cycle activity in cardiomyocytes.
RESUMEN
BACKGROUND: N(ε)-carboxymethyl-lysine (CML) is a major advanced glycation end-product (AGEs) widely found in foods. The aim of our study was to evaluate how exogenous CML-peptide is dynamically absorbed from the gastrointestinal tract and eliminated by renal tubular secretion using microPET imaging. METHODS: The present study consisted of three investigations. In study I, we synthesized the imaging tracer (18)F-CML by reacting N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB) with CML. In study II, the biological activity of (18)F-CML was evaluated in RAW264.7 cells and HepG2 cells. In study III, the biodistribution and elimination of AGEs in ICR mice were studied in vivo following tail vein injection and intragastric administration of (18)F-CML. RESULT: The formation of (18)F-CML was confirmed by comparing its retention time with the corresponding reference compound (19)F-CML. The radiochemical purity (RCP) of (18)F-CML was >95%, and it showed a stable character in vitro and in vivo. Uptake of (18)F-CML by RAW264.7 cells and HepG2 cells could be inhibited by unmodified CML. (18)F-CML was quickly distributed via the blood, and it was rapidly excreted through the kidneys 20 min after tail vein injection. However, (18)F-CML was only slightly absorbed following intragastric administration. After administration of (18)F-CML via a stomach tube, the radioactivity was completely localized in the stomach for the first 15 min. At 150 min post intragastric administration, intense accumulation of radioactivity in the intestines was still observed. CONCLUSIONS: PET technology is a powerful tool for the in vivo analysis of the gastrointestinal absorption of orally administered drugs. (18)F-CML is hardly absorbed by the gastrointestinal tract. It is rapidly distributed and eliminated from blood following intravenous administration. Thus, it may not be harmful to healthy bodies. Our study showed the feasibility of noninvasively imaging (18)F-labeled AGEs and was the first to describe CML-peptide gastrointestinal absorption by means of PET.
Asunto(s)
Radioisótopos de Flúor , Lisina/análogos & derivados , Tomografía de Emisión de Positrones , Administración Intravenosa , Animales , Línea Celular , Radioisótopos de Flúor/química , Células Hep G2 , Humanos , Lisina/administración & dosificación , Lisina/química , Lisina/farmacocinética , Masculino , Ratones , Distribución TisularRESUMEN
OBJECTIVE: To explore the impact and related mechanisms of stromal cell-derived factor-1α (SDF-1α) on serum deprivation-induced apoptosis of cardiac stem cells (CSCs). METHODS: CSCs were isolated from adult mouse heart tissue and cultured in vitro. Obtained cells were purified using magnetic-activated cell sorting (MACS) with c-kit magnetic beads. C-kit(+)CSCs were divided into five groups: normal control group, serum deprivation group, serum deprivation+SDF-1α group, serum deprivation+SDF-1α+AMD3100 group, serum deprivation+SDF-1α+LY294002 group. Cell apoptosis was assessed using the DeadEnd Colorimetric TUNEL System and flow cytometry analyses with an Annexin V-FITC Apoptosis Detection Kit. The viability of CSCs was assessed by CCK-8. The protein expression of Bcl-2 and phosphorylated Akt were detected by Western blot. The caspase-3 activity was determined using caspase-3 Colorimetric Assay Kit. RESULTS: After magnetic separation, more than 85% of cardiosphere derived cells were positive for c-kit expression. Compared with the normal control group, the apoptosis rate of serum deprivation group was significantly increased[(27.03 ± 0.80)% vs. (1.51 ± 0.54)%, P < 0.01], which could be significantly reduced by SDF-1α in a concentration dependent manner and peak effect was seen with 100 ng/ml SDF-1α[(10.67 ± 1.06)% vs. (27.03 ± 0.80)%, P < 0.01]. The expressions of p-Akt and Bcl-2 were significantly increased and the activity of caspase-3 was significantly decreased in serum deprivation+SDF-1α group compared to serum deprivation group (P < 0.01). Further more, the expression of p-Akt and Bcl-2 were significantly decreased and the activity of caspase-3 was increased in both serum deprivation+SDF-1α+AMD3100 group and serum deprivation+SDF-1α+LY294002 group compared to serum deprivation+SDF-1α group (P < 0.01). CONCLUSIONS: SDF-1α reduces serum deprivation induced CSCs apoptosis via modulating PI3K/Akt signaling pathway.