Papel do receptor β1-adrenérgico na modulação da hipertrofia cardíaca induzida pelo hormônio tireoidiano

Abstract

The role of β-adrenergic receptor mediating cardiac hypertrophy in hyperthyroidism is not described in the literature and a better comprehensive approach is needed. The purposes of this study were divided into two stages, which the first one aimed to characterize the pattern of hypertrophy induced by T3. The second stage aimed to assess the β1-adrenergic receptor role in cellular signaling modulation involved in cardiac hypertrophy. The methodology of the first stage was characterized by the T3 administration (i.p.) in male mice for 12 days (n=40), after that the electrocardiographic and heart rate variability analyzes were performed. In the second step wild (WT; n=16) and β1-adrenergic receptor knockout animals (β1KO; n=13) were subjected to a hyperthyroidism protocol (s.c.) for 10 days. Subsequently, the animals underwent echocardiography analysis and post mortem study. The institutional research ethics committee approved this study (protocol # 207/2012). In the first step the protocol significantly increase serum T3 levels and increase Ang I, Ang II and decrease ANP in the heart, confirming the efficiency of the model. The analysis of heart rate variability showed increased sympathetic modulation in animals treated with T3 (p < 0.05). During the second stage, the WT treated developed physiological cardiac hypertrophy, while β1KO developed pathological hypertrophy according to echocardiographic analysis. Plasma and heart ANP levels were dependent to β1-adrenergic receptor (p <0.05). No change was found for plasma and heart levels of Ang I and Ang II between groups (p > 0.05). Targeting the proteins involved in cellular signaling, the β1KO showed less PKA activation in comparison with WT (p < 0.05). The β1KO group treated with T3 showed greater activation of ERK1/2 when compared to other groups. There was not identified difference between groups for Akt activation and 4E-BP1 phosphorylated protein (p > 0.05). Furthermore, activation of p38 was significantly higher in WT treated when compared to their controls or β1KO treated with T3 (p < 0.05). We conclude that T3 protocol is efficient to induce hyperthyroidism, and the β1-adrenergic receptors play a crucial role in modulating physiological cardiac hypertrophy by inhibiting ERK1/2 signaling in the heart, through p38 activation.