RESUMEN
The increase of reactive oxygen species in infracted heart significantly reduces the survival of donor mesenchymal stem cells, thereby attenuating the therapeutic efficacy for myocardial infarction. In our previous study, we demonstrated that lysophosphatidic acid (LPA) protects bone marrow-derived mesenchymal stem cells (BMSCs) against hypoxia and serum deprivation-induced apoptosis. However, whether LPA protects BMSCs from H2O2-induced apoptosis was not examined. In this study, we report that H2O2 induces rat BMSC apoptosis whereas LPA pre-treatment effectively protects BMSCs from H2O2-induced apoptosis. LPA protection of BMSC from the induced apoptosis is mediated mostly through LPA3 receptor. Furthermore, we found that membrane G protein Gi2 and Gi3 are involved in LPA-elicited anti-apoptotic effects through activation of ERK1/2- and PI3 K-pathways. Additionally, H2O2 increases levels of type II of light chain 3B (LC3B II), an autophagy marker, and H2O2-induced autophagy thus protected BMSCs from apoptosis. LPA further increases the expression of LC3B II in the presence of H2O2. In contrast, autophagy flux inhibitor bafilomycin A1 has no effect on LPA's protection of BMSC from H2O2-induced apoptosis. Taken together, our data suggest that LPA rescues H2O2-induced apoptosis mainly by interacting with Gi-coupled LPA3, resulting activation of the ERK1/2- and PI3 K/AKT-pathways and inhibition caspase-3 cleavage, and LPA protection of BMSCs against the apoptosis is independent of it induced autophagy.
Asunto(s)
Apoptosis/efectos de los fármacos , Subunidad alfa de la Proteína de Unión al GTP Gi2/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Peróxido de Hidrógeno/antagonistas & inhibidores , Lisofosfolípidos/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Subunidad alfa de la Proteína de Unión al GTP Gi2/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Peróxido de Hidrógeno/farmacología , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Cultivo Primario de Células , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismoRESUMEN
OBJECTIVE: To investigated the effect of lovastatin on hypoxia and serum deprivation (Hypoxia/SD) induced rat MSCs apoptosis in vitro and associated signaling pathway changes. METHODS: MSCs were isolated from Sprague-Dawley rats. The anti-apoptotic effects of lovastatin were detected using Hoechst33342 and annexin V-FITC/PI binding assay by Flow cytometric analysis. The phosphorylation of Akt and ERK1/2, the cytochrome C and the cleaved caspase-3 were detected by Western blot. RESULTS: Lovastatin (0.01 - 1 micromol/L) significantly reduced Hypoxia/SD-induced MSCs apoptosis and increased Akt phosphorylation, reduced caspase-3 activation and cytochrome c release from mitochondria to cytosol in a time dependent manner. These effects could be significantly blocked by both PI3K inhibitor, LY294002 and ERK1/2 inhibitor, U0126. CONCLUSIONS: Our results showed that lovastatin protects MSCs from Hypoxia/SD-induced apoptosis via activating PI3K/Akt and ERK1/2 signaling pathways suggesting a potential role of statins as an adjunct therapeutic agent during transplanting MSCs into damaged heart after myocardial infarction.
Asunto(s)
Apoptosis/efectos de los fármacos , Lovastatina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Caspasa 3/metabolismo , Hipoxia de la Célula , Células Cultivadas , Citocromos c/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Madre Mesenquimatosas/citología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-DawleyAsunto(s)
Acoplamiento Excitación-Contracción/fisiología , Contracción Miocárdica/fisiología , Animales , Animales Recién Nacidos , Canales de Calcio/fisiología , Corazón/crecimiento & desarrollo , Corazón/fisiología , Humanos , Recién Nacido , Mamíferos/crecimiento & desarrollo , Mamíferos/fisiología , Miocardio/metabolismoRESUMEN
BACKGROUND: Increased red blood cell distribution width (RDW) is associated with adverse outcomes in patients with heart failure (HF). The objective of this study was to compare the differences in the predictive value of RDW in patients with HF due to different causes. METHODS: We retrospectively investigated 1,021 HF patients from October 2009 to December 2011 at Fuwai Hospital (Beijing, China). HF in these patients was caused by three diseases; coronary heart disease (CHD), dilated cardiomyopathy (DCM) and valvular heart disease (VHD). Patients were followed-up for 21 ± 9 months. RESULTS: The RDW, mortality and survival duration were significantly different among the three groups. Kaplan-Meier analysis showed that the cumulative survival decreased significantly with increased RDW in patients with HF caused by CHD and DCM, but not in those with HF patients caused by VHD. In a multivariable model, RDW was identified as an independent predictor for the mortality of HF patients with CHD (P < 0.001, HR 1.315, 95% CI 1.122-1.543). The group with higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and higher RDW than median had the lowest cumulative survival in patients with HF due to CHD, but not in patients with HF due to DCM. CONCLUSIONS: RDW is a prognostic indicator for patients with HF caused by CHD and DCM; thus, RDW adds important information to NT-proBNP in CHD caused HF patients.
RESUMEN
RATIONALE AND OBJECTIVES: The aim of this study was to evaluate whether matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) are elevated in patients with nonobstructive coronary artery disease. MATERIALS AND METHODS: Eighty-four patients with nonobstructive coronary artery disease (group A) and 90 patients with no coronary plaques (group B) were enrolled. MMP-9 and MPO levels were compared between the two groups. The relationships between these biomarkers and Framingham risk score were analyzed. Receiver-operating characteristic curves were used to evaluate the ability of these biomarkers to predict the presence of coronary artery plaques. RESULTS: The MMP-9 and MPO values in group A were significantly higher than in group B (P < .001). The levels of MMP-9 and MPO showed significant correlations with Framingham risk score (r = 0.796, P < .001, and r = 0.409, P < .001, respectively). The areas under the receiver-operating characteristic curves for MMP-9 and MPO were 0.80 (95% confidence interval, 0.74-0.87) and 0.74 (95% confidence interval, 0.66-0.81), respectively. CONCLUSIONS: Levels of MMP-9 and MPO are positively correlated with Framingham risk score. Additionally, in patients with nonobstructive coronary artery disease, elevated levels of MMP-9 and MPO may identify patients at risk for future myocardial infarction or sudden cardiac death.
Asunto(s)
Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Peroxidasa/metabolismo , Tomografía Computarizada por Rayos X , Biomarcadores , Medios de Contraste , Femenino , Humanos , Yohexol/análogos & derivados , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
The use of bone marrow mesenchymal stem cell- (MSC) transplantation therapy for cardiac diseases is limited due to poor survival of implanted cells. MicroRNAs (miRNAs) have been reported to be involved in regulating almost all cellular processes, including apoptosis. In this study, we found that the miRNA profile was altered during apoptosis induced by hypoxia and serum deprivation (hypoxia/SD). We further revealed that over-expression of miR-21, miR-23a and miR-210 could promote the survival of MSCs exposed to hypoxia/SD. In contrast, down-regulation of miR-21, miR-23a and miR-503 aggravated apoptosis of MSCs. It was indicated that these miRNAs may play important roles during MSC apoptosis induced by hypoxia/SD.