RESUMEN
AIMS: Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Gαi2 knockout on cardiac function and survival in a murine heart failure model of cardiac ß1-adrenoceptor overexpression. METHODS AND RESULTS: ß1-transgenic mice lacking Gαi2 (ß1-tg/Gαi2 (-/-)) were compared with wild-type mice and littermates either overexpressing cardiac ß1-adrenoceptors (ß1-tg) or lacking Gαi2 (Gαi2 (-/-)). At 300 days, mortality of mice only lacking Gαi2 was already higher compared with wild-type or ß1-tg, but similar to ß1-tg/Gαi2 (-/-), mice. Beyond 300 days, mortality of ß1-tg/Gαi2 (-/-) mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, ß1-tg, and Gαi2 (-/-) mice, but significant impairment for ß1-tg/Gαi2 (-/-) mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gαi3 was significantly up-regulated in Gαi2 knockout mice (protein compared with wild type: 340 ± 90% in Gαi2 (-/-) and 394 ± 80% in ß1-tg/Gαi2 (-/-), respectively). CONCLUSIONS: Gαi2 deficiency combined with cardiac ß1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, ß1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gαi2. We propose an enhanced effect of increased ß1-adrenergic drive by the lack of protection via Gαi2. Gαi3 up-regulation was not sufficient to compensate for Gαi2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.
Asunto(s)
Cardiomiopatía Dilatada/metabolismo , Subunidad alfa de la Proteína de Unión al GTP Gi2/deficiencia , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Subunidad alfa de la Proteína de Unión al GTP Gi2/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/patología , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Fenotipo , Receptores Adrenérgicos beta 1/genética , Volumen Sistólico , Factores de Tiempo , Ultrasonografía , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
Anecdotal evidence abounds that organizations have distinct conflict cultures, or socially shared norms for how conflict should be managed. However, research to date has largely focused on conflict management styles at the individual and small group level, and has yet to examine whether organizations create socially shared and normative ways to manage conflict. In a sample of leaders and members from 92 branches of a large bank, factor analysis and aggregation analyses show that 3 conflict cultures-collaborative, dominating, and avoidant-operate at the unit level of analysis. Building on Lewin, Lippitt, and White's (1939) classic work, we find that leaders' own conflict management behaviors are associated with distinct unit conflict cultures. The results also demonstrate that conflict cultures have implications for macro branch-level outcomes, including branch viability (i.e., cohesion, potency, and burnout) and branch performance (i.e., creativity and customer service). A conflict culture perspective moves beyond the individual level and provides new insight into the dynamics of conflict management in organizational contexts.
Asunto(s)
Conflicto Psicológico , Procesos de Grupo , Relaciones Interpersonales , Liderazgo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cultura OrganizacionalRESUMEN
Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression-related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype.