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1.
Neurorehabil Neural Repair ; 37(4): 240-250, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37083157

RESUMEN

BACKGROUND: Evidence showed that patients with Parkinson's disease (PD) who have a history of freezing of gait (FOG) have hypometric anticipatory postural adjustment (APA) during gait initiation (GI) compared to PD without FOG. OBJECTIVES: This study aimed to test the feasibility of center of pressure (COP) displacement during GI as the measure of APA in PD with and without a history of FOG. METHODS: Patients with PD underwent COP trajectory measurements, including duration, length, velocity, and acceleration in different phases of APA (APA1, APA2a, APA2, and LOC), as well as evaluation of New Freezing of Gait Questionnaire (NFOG-Q), Tinetti balance and gait score, and Postural Instability and Gait Difficulty (PIGD) score in the on and off medication states. RESULTS: The duration (seconds) of APA2a, APA2b, and LOC were highest while velocity in mediolateral direction (X) (m/s), including APA1, APA2a, APA2b, and LOC showed lowest in PD with FOG. Velocity in the mediolateral direction in different phases of APA increased in patients with FOG after dopaminergic therapy. APA2a (seconds) and APA2b (X) (m/s) were significantly associated with NFOG-Q part II, APA2b (X) (m/s) was significantly associated with NFOG-Q part III, and APA2a (seconds) was significantly associated with Tinetti balance and gait and PIGD score. CONCLUSIONS: PD with FOG history showed a favorable response of APAs to dopaminergic replacement. The APA parameters by COP trajectory, especially lateral COP shift toward the stance foot (APA2b (X) (m/s) and APA2a (seconds)) are surrogate markers to assess PD with FOG history.


Asunto(s)
Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Trastornos Neurológicos de la Marcha/complicaciones , Equilibrio Postural/fisiología , Marcha/fisiología , Cognición , Dopamina
2.
Sci Rep ; 12(1): 4337, 2022 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-35288601

RESUMEN

Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients. Here, we used previously published cMyBP-C peptides 302A and 302S, surrogates of the regulatory phosphorylation site serine 302, as a tool to determine the effects of modulating the dephosphorylation state of cMyBP-C on cardiac contraction and relaxation in experimental heart failure (HF) models in vitro. Both peptides increased the contractility of papillary muscle fibers isolated from a mouse model expressing cMyBP-C phospho-ablation (cMyBP-CAAA) constitutively. Peptide 302A, in particular, could also improve the force redevelopment rate (ktr) in papillary muscle fibers from cMyBP-CAAA (nonphosphorylated alanines) mice. Consistent with the above findings, both peptides increased ATPase rates in myofibrils isolated from rats with myocardial infarction (MI), but not from sham rats. Furthermore, in the cMyBP-CAAA mouse model, both peptides improved ATPase hydrolysis rates. These changes were not observed in non-transgenic (NTG) mice or sham rats, indicating the specific effects of these peptides in regulating the dephosphorylation state of cMyBP-C under the pathological conditions of HF. Taken together, these studies demonstrate that modulation of cMyBP-C dephosphorylation state can be a therapeutic approach to improve myosin function, sarcomere contractility and relaxation after an adverse cardiac event. Therefore, targeting cMyBP-C could potentially improve overall cardiac performance as a complement to standard-care drugs in HF patients.


Asunto(s)
Insuficiencia Cardíaca , Miocardio , Animales , Miosinas Cardíacas/metabolismo , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto/metabolismo , Humanos , Ratones , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Miosinas/metabolismo , Péptidos/metabolismo , Fosforilación/fisiología , Ratas
3.
PLoS One ; 17(1): e0261000, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35085251

RESUMEN

BACKGROUND: Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. MATERIALS AND METHODS: The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. RESULTS: While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. CONCLUSION: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy.


Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Enalaprilato/administración & dosificación , Activadores de Enzimas/administración & dosificación , Guanilil Ciclasa Soluble/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Cricetulus , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Enalaprilato/farmacología , Activadores de Enzimas/farmacología , Perfilación de la Expresión Génica , Pruebas de Función Renal , Masculino , Óxido Nítrico/metabolismo , Estrés Oxidativo , Proyectos Piloto , Ratas , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
4.
Nature ; 433(7026): 647-53, 2005 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-15703750

RESUMEN

The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unravelling steps for cardiac cell lineage formation, and their links to forms of congenital and adult cardiac diseases. Until now there has been little evidence for native cardiac precursor cells in the postnatal heart. Herein, we report the identification of isl1+ cardiac progenitors in postnatal rat, mouse and human myocardium. A cardiac mesenchymal feeder layer allows renewal of the isolated progenitor cells with maintenance of their capability to adopt a fully differentiated cardiomyocyte phenotype. Tamoxifen-inducible Cre/lox technology enables selective marking of this progenitor cell population including its progeny, at a defined time, and purification to relative homogeneity. Co-culture studies with neonatal myocytes indicate that isl1+ cells represent authentic, endogenous cardiac progenitors (cardioblasts) that display highly efficient conversion to a mature cardiac phenotype with stable expression of myocytic markers (25%) in the absence of cell fusion, intact Ca2+-cycling, and the generation of action potentials. The discovery of native cardioblasts represents a genetically based system to identify steps in cardiac cell lineage formation and maturation in development and disease.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Proteínas de Homeodominio/análisis , Mioblastos Cardíacos/citología , Mioblastos Cardíacos/metabolismo , Miocardio/citología , Proteínas del Tejido Nervioso/análisis , Potenciales de Acción , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Calcio/metabolismo , Señalización del Calcio , Fusión Celular , Células Cultivadas , Técnicas de Cocultivo , Marcadores Genéticos/genética , Corazón/embriología , Corazón/crecimiento & desarrollo , Proteínas de Homeodominio/metabolismo , Humanos , Proteínas con Homeodominio LIM , Ratones , Miocardio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Ratas , Factores de Transcripción
5.
Nat Biotechnol ; 25(9): 1015-24, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17721512

RESUMEN

Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell-derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell-derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.


Asunto(s)
Células Madre Embrionarias/citología , Supervivencia de Injerto , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Miocardio/patología , Miocitos Cardíacos/citología , Animales , Diferenciación Celular , Movimiento Celular , Supervivencia Celular , Ecocardiografía , Ventrículos Cardíacos/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Miocitos Cardíacos/trasplante , Ratas , Ratas Sprague-Dawley
6.
PLoS One ; 15(8): e0231234, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32804947

RESUMEN

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.


Asunto(s)
Factor 15 de Diferenciación de Crecimiento/metabolismo , Factor 15 de Diferenciación de Crecimiento/farmacología , Síndrome Metabólico/metabolismo , Animales , Biomarcadores/metabolismo , Corazón/fisiología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Riñón/metabolismo , Masculino , Síndrome Metabólico/complicaciones , Miocardio/metabolismo , Obesidad/complicaciones , Ratas , Ratas Endogámicas , Ratas Zucker , Volumen Sistólico/fisiología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología
7.
JCI Insight ; 5(8)2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32208384

RESUMEN

Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has the potential to be a novel target to treat HF. Intravenous administration of apelin improves cardiac function acutely in patients with HF. However, its short half-life restricts its use to infusion therapy. To identify a longer acting APJ agonist, we conducted a medicinal chemistry campaign, leading to the discovery of potent small-molecule APJ agonists with comparable activity to apelin by mimicking the C-terminal portion of apelin-13. Acute infusion increased systolic function and reduced systemic vascular resistance in 2 rat models of impaired cardiac function. Similar results were obtained in an anesthetized but not a conscious canine HF model. Chronic oral dosing in a rat myocardial infarction model reduced myocardial collagen content and improved diastolic function to a similar extent as losartan, a RAS antagonist standard-of-care therapy, but lacked additivity with coadministration. Collectively, this work demonstrates the feasibility of developing clinical, viable, potent small-molecule agonists that mimic the endogenous APJ ligand with more favorable drug-like properties and highlights potential limitations for APJ agonism for this indication.


Asunto(s)
Receptores de Apelina/agonistas , Corazón/efectos de los fármacos , Animales , Perros , Descubrimiento de Drogas , Insuficiencia Cardíaca , Péptidos y Proteínas de Señalización Intercelular , Ratas
8.
Int J Oncol ; 55(4): 949-959, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31485602

RESUMEN

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Despite advances in surgery, radiotherapy and chemotherapy, the overall 5­year survival rate of patients with OSCC has not significantly improved. In addition, the prognosis of patients with advanced­stage OSCC remains poor. Therefore, it is necessary to develop novel therapeutic modalities. Vincristine (VCR), a naturally occurring vinca alkaloid, is a classical microtubule­destabilizing agent and is widely used in the treatment of a number of cancers. Despite the proven antitumor benefits of VCR treatment, one of the major reasons for the failure of treatment is drug resistance. Changes in the tumor microenvironment are responsible for cross­talk between cells, which may facilitate drug resistance in cancers; secreted proteins may promote communication between cancer cells to induce the development of resistance. To identify the secreted proteins involved in VCR resistance, conditioned media was obtained, and an antibody array was conducted to screen a comprehensive secretion profile between VCR­resistant (SAS­VCR) and parental (SAS) OSCC cell lines. The results showed that amphiregulin (AREG) was highly expressed and secreted in SAS­VCR cells. Pretreatment with exogenous recombinant AREG markedly increased drug resistance against VCR in OSCC cells, as assessed by an MTT assay. Colony formation, MTT and western blot assays were performed to investigate the effects of AREG knockdown on VCR sensitivity. The results indicated that AREG expression can regulate VCR resistance in OSCC cells; overexpression of AREG increased VCR resistance in parental cells, whereas AREG knockdown decreased the VCR resistance of resistant cells. In addition, it was also demonstrated that the glycogen synthase kinase­3ß pathway may be involved in AREG­induced VCR resistance. These findings may provide rationale to combine VCR with blockade of AREG­related pathways for the effective treatment of OSCC.


Asunto(s)
Anfirregulina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Resistencia a Antineoplásicos , Neoplasias de la Boca/metabolismo , Anfirregulina/genética , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Medios de Cultivo Condicionados/farmacología , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Pronóstico , Transducción de Señal , Regulación hacia Arriba , Vincristina/farmacología
9.
Circulation ; 114(10): 1046-55, 2006 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-16923756

RESUMEN

BACKGROUND: alpha-E-catenin is a cell adhesion protein, located within the adherens junction, thought to be essential in directly linking the cadherin-based adhesion complex to the actin cytoskeleton. Although alpha-E-catenin is expressed in the adherens junction of the cardiomyocyte intercalated disc, and perturbations in its expression are observed in models of dilated cardiomyopathy, its role in the myocardium remains unknown. METHODS AND RESULTS: To determine the effects of alpha-E-catenin on cardiomyocyte ultrastructure and disease, we generated cardiac-specific alpha-E-catenin conditional knockout mice (alpha-E-cat cKO). alpha-E-cat cKO mice displayed progressive dilated cardiomyopathy and unique defects in the right ventricle. The effects on cardiac morphology/function in alpha-E-cat cKO mice were preceded by ultrastructural defects in the intercalated disc and complete loss of vinculin at the intercalated disc. alpha-E-cat cKO mice also revealed a striking susceptibility of the ventricular free wall to rupture after myocardial infarction. CONCLUSIONS: These results demonstrate a clear functional role for alpha-E-catenin in the cadherin/catenin/vinculin complex in the myocardium in vivo. Ablation of alpha-E-catenin within this complex leads to defects in cardiomyocyte structural integrity that result in unique forms of cardiomyopathy and predisposed susceptibility to death after myocardial stress. These studies further highlight the importance of studying the role of alpha-E-catenin in human cardiac injury and cardiomyopathy in the future.


Asunto(s)
Cardiomiopatía Dilatada/genética , Células Musculares/fisiología , Infarto del Miocardio/genética , Disfunción Ventricular Derecha/genética , alfa Catenina/genética , Animales , Modelos Animales de Enfermedad , Electrocardiografía , Ratones , Ratones Noqueados , Células Musculares/patología , Miocardio/patología , Proteínas/metabolismo , alfa Catenina/deficiencia
10.
Cardiovasc Toxicol ; 2(2): 119-27, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12271155

RESUMEN

The incidence of myocardial infarction in patients who have the aquired immunodeficiency syndrome (AIDS) is increasing. However, no effective therapeutic agents have been discovered to reduce myocardial ischemia-reperfusion (I/R) injury in pathologies associated with AIDS. The aim of this study was to determine if infarct size is increased in murine AIDS after I/R injury and if I/R injury could be attenuated with vitamin E supplementation. Three groups of mice were studied: control, murine AIDS, and murine AIDS with vitamin E supplementation. Anesthetized mice were subjected to 30 min of left anterior descending coronary artery occlusion and 120 min of reperfusion. The hearts in mice that had murine AIDS had a larger infarct size compared to controls after I/R injury. Vitamin E supplementation significantly reduced infarct size and inhibited polymorphonuclear neutrophil (PMN) CD11b expression (p < 0.05). However, vitamin E supplementation did not affect PMN reactive oxygen species (ROS) production and platelet CD62p expression. These results suggest that the reduction of myocardial I/R injury with vitamin E supplementation may be the result of the inhibition of PMN CD11b expression. Vitamin E may be a promising prophylactic agent for the reduction of the severity of myocardial I/R injury in patients who have AIDS.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Antioxidantes/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/etiología , Daño por Reperfusión Miocárdica/complicaciones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Vitamina E/farmacología , Síndrome de Inmunodeficiencia Adquirida/metabolismo , Adenosina Difosfato/farmacología , Animales , Antígeno CD11b/biosíntesis , Antígeno CD11b/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ventrículos Cardíacos/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Cardiovasculares , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Isquemia Miocárdica/epidemiología , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Miocardio/patología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Selectina-P/biosíntesis , Selectina-P/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo
11.
Cogn Neurodyn ; 8(3): 177-97, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24808928

RESUMEN

Extracellular electric fields existing throughout the living brain affect the neural coding and information processing via ephaptic transmission, independent of synapses. A two-compartment whole field effect model (WFEM) of pyramidal neurons embedded within a resistive array which simulates the extracellular medium i.e. ephapse is developed to study the effects of electric field on neuronal behaviors. We derive the two linearized filed effect models (LFEM-1 and LFEM-2) from WFEM at the stable resting state. Through matching these simplified models to the subthreshold membrane response in experiments of the resting pyramidal cells exposed to applied electric fields, we not only verify our proposed model's validity but also found the key parameters which dominate subthreshold frequency response characteristic. Moreover, we find and give its underlying biophysical mechanism that the unsymmetrical properties of active ion channels results in the very different low-frequency response of somatic and dendritic compartments. Following, WFEM is used to investigate both direct-current (DC) and alternating-current field effect on the neural firing patterns by bifurcation analyses. We present that DC electric field could modulate neuronal excitability, with the positive field improving the excitability, the modest negative field suppressing the excitability, but interestingly, the larger negative field re-exciting the neuron back into spiking behavior. The neuron exposed to the sinusoidal electric field exhibits abundant firing patterns sensitive to the input frequency and intensity. In addition, the electrical properties of ephapse can modulate the efficacy of field effect. Our simulated results are qualitatively in line with the relevant experimental results and can explain some experimental phenomena. Furthermore, they are helpful to provide the predictions which can be tested in future experiments.

12.
Regen Med ; 6(1): 53-66, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21175287

RESUMEN

AIM: Human embryonic stem cells (hESCs) represent a novel cell source to treat diseases such as heart failure and for use in drug screening. In this study, we aim to promote efficient generation of cardiomyocytes from hESCs by combining the current optimal techniques of controlled growth of undifferentiated cells and specific induction for cardiac differentiation. We also aim to examine whether these methods are scalable and whether the differentiated cells can be cryopreserved. METHODS & RESULTS: hESCs were maintained without conditioned medium or feeders and were sequentially treated with activin A and bone morphogenetic protein-4 in a serum-free medium. This led to differentiation into cell populations containing high percentages of cardiomyocytes. The differentiated cells expressed appropriate cardiomyocyte markers and maintained contractility in culture, and the majority of the cells displayed working chamber (atrial and ventricular) type electrophysiological properties. In addition, the cell growth and differentiation process was adaptable to large culture formats. Moreover, the cardiomyocytes survived following cryopreservation, and viable cardiac grafts were detected after transplantation of cryopreserved cells into rat hearts following myocardial infarctions. CONCLUSION: These results demonstrate that cardiomyocytes of high quality can be efficiently generated and cryopreserved using hESCs maintained in serum-free medium, a step forward towards the application of these cells to human clinical use or drug discovery.


Asunto(s)
Criopreservación/métodos , Células Madre Embrionarias/citología , Miocitos Cardíacos , Animales , Diferenciación Celular , Línea Celular , Proliferación Celular , Medio de Cultivo Libre de Suero , Humanos , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Ratas
13.
Cell ; 127(6): 1151-65, 2006 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17123592

RESUMEN

Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1(+) precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1(+) cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1(+)/Nkx2.5(+)/flk1(+) defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1(+) cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.


Asunto(s)
Células Madre Embrionarias/fisiología , Células Endoteliales/citología , Proteínas de Homeodominio/genética , Células Madre Multipotentes/fisiología , Miocardio/citología , Miocitos Cardíacos/citología , Miocitos del Músculo Liso/citología , Animales , Técnicas de Cultivo de Célula , Diferenciación Celular , Linaje de la Célula , Células Clonales , Corazón/embriología , Heterocigoto , Proteínas con Homeodominio LIM , Ratones , Ratones Endogámicos , Factores de Transcripción
14.
Alcohol Alcohol ; 37(6): 555-60, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12414546

RESUMEN

BACKGROUND AND AIMS: The cardiovascular complications of AIDS are serious. However, the underlying mechanisms are unclear. Less is known about how ethanol affects the coronary microcirculation in individuals with AIDS. The aim of this study was to assess the integrity of the coronary microcirculation in murine AIDS mice in the presence or absence of chronic ethanol consumption. METHODS: Four groups were studied: control, murine AIDS, ethanol and ethanol plus murine AIDS. Mouse hearts were prepared for direct visualization of the coronary microcirculation and quantification of trans-coronary macromolecular leakage. Hearts were isolated and perfused with diluted rat blood containing fluorescein isothiocyanate-albumin (FITC-BSA). Coronary vessels were observed using intravital fluorescence microscopy after 5, 15 and 25 min of perfusion. The mean luminosity of outside/inside coronary vessels (O/I ratio) was used to quantify FITC-BSA leakage. RESULTS: We found that the mean O/I ratio for the murine AIDS group was significantly greater than in the control group and also significantly increased during the perfusion period. Chronic ethanol consumption did not alter coronary permeability to macromolecules, but improved the coronary haemodynamics in murine AIDS. CONCLUSIONS: These findings suggest that murine AIDS impairs the structural and functional coronary endothelium, and moderate ethanol consumption modulates the function of the coronary microcirculation.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Depresores del Sistema Nervioso Central/farmacología , Circulación Coronaria/efectos de los fármacos , Etanol/farmacología , Microcirculación/efectos de los fármacos , Análisis de Varianza , Animales , Circulación Coronaria/fisiología , Femenino , Sustancias Macromoleculares , Ratones , Ratones Endogámicos C57BL , Microcirculación/fisiología , Microscopía Fluorescente , Permeabilidad
15.
Alcohol Alcohol ; 38(1): 25-30, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12554603

RESUMEN

AIMS: Abnormal platelet counts have been noticed in acquired immune deficiency syndrome (AIDS) patients. However, the actual state of platelets in AIDS is unclear. We hypothesize that platelets are activated and platelet-derived microparticles increase in murine AIDS. METHODS: To elucidate the ethanol effects on platelets in murine AIDS, we studied four groups: control, murine AIDS, ethanol, and ethanol plus murine AIDS. Platelet CD62p as a platelet activation marker and CD61(+) microparticles as platelet microparticles (PMPs) were measured by flow cytometry. RESULTS: Platelets were significantly activated in mice with murine AIDS and chronic ethanol consumption. Increased platelet CD62p expression and increased PMPs were most pronounced in advanced stages of murine AIDS. Chronic ethanol consumption persistently enhanced platelet activation and PMP formation. CONCLUSIONS: Elevated platelet CD62p and PMPs may represent a pro-thrombotic status that have important pathological consequences.


Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Alcoholismo/sangre , Síndrome de Inmunodeficiencia Adquirida del Murino/sangre , Selectina-P/sangre , Activación Plaquetaria/efectos de los fármacos , Consumo de Bebidas Alcohólicas/sangre , Animales , Plaquetas/efectos de los fármacos , Femenino , Citometría de Flujo , Cuerpos de Inclusión/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Recuento de Plaquetas
16.
Alcohol Alcohol ; 38(1): 18-24, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12554602

RESUMEN

AIMS: The severity of cardiovascular complications in acquired immune deficiency syndrome (AIDS) patients may be associated with acute ischaemia-reperfusion injury. Epidemiological studies suggest that moderate ethanol consumption has myocardial protective effects. However, it is unknown if chronic ethanol consumption benefits acute myocardial ischaemia-reperfusion injury in AIDS. The aim of this study was to determine if chronic ethanol consumption modulates myocardial ischaemia-reperfusion injury in murine AIDS. METHODS: Four groups were studied: control, murine AIDS, ethanol, and ethanol plus murine AIDS. All mice were subjected to 30 min of left anterior descending branch (LAD) occlusion and 120 min of reperfusion. RESULTS: We found that the survival from an acute myocardial infarction was reduced in advanced-stage murine AIDS mice. Although early-stage murine AIDS hearts did survive in acute myocardial infarction, the infarct size was significantly larger. Chronic ethanol consumption significantly decreased infarct size compared to the control group. Chronic ethanol consumption also improved the survival of murine AIDS mice from an acute myocardial infarction. However, chronic ethanol consumption did not significantly reduce infarct size in murine AIDS. CONCLUSIONS: Our results indicate that multiple deleterious effects may enhance acute ischaemia-reperfusion injury in murine AIDS. The beneficial effects of chronic ethanol consumption in myocardial ischaemia-reperfusion injury may be due to modulation of neutrophil adhesion molecule expression and cytokine secretion.


Asunto(s)
Consumo de Bebidas Alcohólicas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Infarto del Miocardio/inmunología , Daño por Reperfusión Miocárdica/inmunología , Activación Neutrófila/efectos de los fármacos , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/patología , Animales , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/inmunología , Cardiomiopatías/patología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Cómputos Matemáticos , Ratones , Ratones Endogámicos BALB C , Síndrome de Inmunodeficiencia Adquirida del Murino/patología , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Miocardio/inmunología , Miocardio/patología , Activación Neutrófila/inmunología
17.
Alcohol Alcohol ; 38(2): 109-14, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12634256

RESUMEN

AIMS: Neutrophil adhesion molecule CD11b and reactive oxygen species (ROS) are neutrophil activation markers for evaluating the functional activity of neutrophils. The aim of this study was to determine if neutrophils are activated in murine AIDS and/or chronic ethanol consumption and if neutrophil CD11b expression and ROS production vary when progressive retrovirus infection occurs. METHODS: Four groups were studied: control, murine AIDS, ethanol and ethanol plus murine AIDS. Neutrophil activation was assessed by CD11b expression and ROS production using flow cytometry. RESULTS: We found that neutrophils lost their responsiveness to fMLP due to retrovirus or ethanol exposure. In the murine AIDS group, neutrophil CD11b expression was up-regulated along with a significant increase in ROS after 1 month of retroviral infection. After 2 months, neutrophil CD11b and ROS decreased. However, neutrophil CD11b expression further increased after 3 months. In the ethanol consumption group, neutrophil CD11b expression was down-regulated after 2 months, whereas ROS production increased in the first and third months. In the murine AIDS plus ethanol group, there were significant increases in both ROS and CD11b expression during the 3-month observation period. CONCLUSIONS: These findings suggest that neutrophil function is impaired by LP-BM5 retrovirus infection and/or chronic ethanol consumption. The pattern of neutrophil CD11b expression and ROS production might help to predict the stage of murine AIDS. Ethanol may further compromise neutrophil function in AIDS.


Asunto(s)
Alcoholismo/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Activación Neutrófila/fisiología , Neutrófilos/fisiología , Administración Oral , Análisis de Varianza , Animales , Antígeno CD11b/metabolismo , Etanol/administración & dosificación , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Especies Reactivas de Oxígeno/metabolismo
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