B-adrenoceptor signal transduction in high-output heart failure due to aortocaval shunt in rat

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Wang, Xi
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The failing heart is characterized by blunted B-adrenoceptor (B-AR) responses associated with a number of changes in the signal transduction pathway including downregulation of B-ARs, increased expression of inhibitory G-proteins and G-protein coupled receptor kinases (GRKs) and impaired adenylyl cyclase (AC) activities. However, a careful review of the literature reveals that most types of heart failure in human and experimental models used to study B-AR signaling are associated with low cardiac output heart failure with significant fibrosis in the myocardium. No information is available regarding the regulation of B-AR signal transduction in heart failure with a high-output status without fibrosis. Therefore, the objective of this work is to use a high-output heart failure model without fibrosis and examine the status of B-AR signaling. To reach this aim, we first characterized a high-output model induced by an aortocaval shunt from several aspects including general features, morphology and histology of the heart, circulatory congestion, hemodynamics and contractile function in vivo and in vitro. The results demonstrated that the development of hypertrophy and heart failure typically occurred in three stages: developing hypertrophic stage (first two weeks after the induction of shunt), established hypertrophic stage (2-8 weeks) and decompensated hypertrophic or failing stage (8-16 weeks). The failing stage is characterized by dramatic hypertrophy of both left (LV) and right (RV) ventricles with signs of circulatory congestion, decreased in vivo and in vitro cardiac performance and shift of myosin heavy chain isoforms. However, the response of the failing heart to B-AR stimulation was not blunted but instead showed stimulation of contractile function. To investigate the mechanisms underlying the enhanced B-AR response in aortocaval shunted animals, we examined changes at the receptor level. Agonist binding experiments showed a selective increase in density of B 1-AR but not B2-AR, without any changes in the affinities. Western blot experiments confirmed that the increase in B1-AR density is due to an enhanced expression of protein levels rather than an increased externalization of receptors. However, the steady state mRNA level of B1-AR was not altered indicating an increased translational rate or decreased protein degradation underlying the increased B 1-AR protein expression.