RESUMEN
Reduced function of the cardiac ryanodine receptor or calsequestrin causes catecholaminergic ventricular tachycardia (VT). These proteins regulate sarcoplasmic Ca(2+) release in close conjunction with two accessory proteins, triadin and junctin. Based on data from cardiomyocytes, we hypothesized that enhanced triadin expression could cause VT. We assessed arrhythmias and electrophysiological changes in vivo and in the beating heart in mice expressing junctin, triadin, or both proteins (TRDxJCN), and measured calcium transients in isolated ventricular cardiomyocytes. TRDxJCN mice were studied to compensate the down-regulation of junctin expression in triadin-expressing mice. Exercise or stress provoked repetitive VT in freely roaming TRDxJCN mice whenever heart rate increased above approximately 600 bpm (p<0.05 vs. the three other genotypes). TRDxJCN mice expressed total triadin 2.9-fold (p<0.05) and total junctin not different to wildtype (p=ns). Left ventricular systolic function was not different between lineages. beta-adrenoreceptor stimulation (orciprenaline 1.7 microM) provoked early-coupled ventricular ectopy and repetitive VT in isolated, Langendorff-perfused TRDxJCN hearts (p<0.05). Under conditions associated with VT (high pacing rate, catecholamine stimulation), action potential duration was shorter in TRDxJCN with VT than in the other genotypes and shorter than in TRDxJCN hearts without VT (p<0.05). Ca(2+) transient duration was prolonged in Indo1-loaded TRDxJCN cardiomyocytes under VT-provoking conditions. Action potential prolongation by mexiletine (2 microM or 4 microM) or clarithromycine (150 microM) suppressed VT. Expression of triadin provokes stress- and tachycardia-related ventricular arrhythmias in mice. An imbalance between prolonged intracellular calcium release and shortening of the ventricular action potential may contribute to genesis of arrhythmias in this model.
Asunto(s)
Proteínas Portadoras/genética , Frecuencia Cardíaca , Corazón/fisiología , Proteínas Musculares/genética , Esfuerzo Físico , Taquicardia Ventricular/fisiopatología , Potenciales de Acción , Animales , Proteínas de Unión al Calcio/genética , Cruzamientos Genéticos , Femenino , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Oxigenasas de Función Mixta/genéticaRESUMEN
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. METHODS AND RESULTS: Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin+/-) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P<0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin+/- hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin+/- mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. CONCLUSIONS: Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.
Asunto(s)
Envejecimiento/fisiología , Displasia Ventricular Derecha Arritmogénica/etiología , Desmosomas/patología , Modelos Animales de Enfermedad , Condicionamiento Físico Animal/efectos adversos , gamma Catenina/deficiencia , Animales , Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Electrocardiografía , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Glucosa/metabolismo , Heterocigoto , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/patología , Ratones , Ratones Noqueados , Modelos Cardiovasculares , Contracción Miocárdica , Miocardio/metabolismo , Miocardio/ultraestructura , Fenotipo , Estrés Fisiológico/fisiopatología , Natación , Taquicardia Ventricular/etiología , Taquicardia Ventricular/genética , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/genética , Complejos Prematuros Ventriculares/etiología , Complejos Prematuros Ventriculares/genética , gamma Catenina/genéticaRESUMEN
Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model. G-CSF/SCF improved cardiac output after myocardial infarction. Although G-CSF/SCF led to a twofold increased, potentially proarrhythmic homing of bone marrow (BM)-derived cells to the area of infarction, <1% of these cells adopted a cardial phenotype. Inducibility of ventricular tachycardias during programmed stimulation was reduced 5 wk after G-CSF/SCF treatment. G-CSF/SCF increased cardiomyocyte diameter, arteriogenesis, and expression of connexin43 in the border zone of the infarction. An enhanced expression of the G-CSF receptor demonstrated in cardiomyocytes and other cell types of the infarcted myocardium indicates a sensitization of the heart to direct influences of this cytokine. In addition to paracrine effects potentially caused by the increased homing of BM-derived cells, these might contribute to the therapeutic effects of G-CSF.
Asunto(s)
Arritmias Cardíacas/prevención & control , Factor Estimulante de Colonias de Granulocitos/farmacología , Infarto del Miocardio/metabolismo , Factor de Células Madre/farmacología , Animales , Trasplante de Médula Ósea , Gasto Cardíaco/efectos de los fármacos , Conexina 43/metabolismo , Modelos Animales de Enfermedad , Femenino , Corazón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na+/H+ exchanger NHE-1 to cardiac remodeling in GC-A-deficient (GC-A(-/-)) mice. METHODS AND RESULTS: Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A(-/-) mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca2+ levels. Chronic treatment of GC-A(-/-) mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A(-/-) mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca2+/calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A(-/-) mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy. CONCLUSIONS: On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca2+, and CaMKII as well as Akt activity.
Asunto(s)
Cardiomegalia/genética , Corazón/fisiología , Receptores del Factor Natriurético Atrial/fisiología , Intercambiadores de Sodio-Hidrógeno/fisiología , Actinas/genética , Animales , Sondas de ADN , Modelos Animales de Enfermedad , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Hemodinámica/fisiología , Ratones , Ratones Noqueados , Células Musculares/citología , Células Musculares/fisiología , Contracción Miocárdica , ARN/genética , ARN/aislamiento & purificación , Receptores del Factor Natriurético Atrial/deficiencia , Receptores del Factor Natriurético Atrial/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de SecuenciaRESUMEN
Atrial natriuretic peptide (ANP), via its vasodilating and diuretic effects, has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance of this is controversial. To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination. Notably, despite full preservation of the direct vasodilating effects of ANP, mice with endothelium-restricted deletion of the GC-A gene (EC GC-A KO) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations together with the Evan's blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11-13%, even under conditions of normal dietary salt intake. Infusion of ANP caused immediate increases in hematocrit in control but not in EC GC-A KO mice, which indicated that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume produced by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice. We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.