alpha(1A)-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion

作者:Papay Robert S; Shi Ting; Piascik Michael T; Prasad Sathyamangla V Naga; Perez Dianne M*
来源:Molecular Pharmacology, 2013, 83(5): 939-948.
DOI:10.1124/mol.112.084483

摘要

The role of alpha(1)-adrenergic receptors (ARs) in the regulation of cardiac hypertrophy is still unclear, because transgenic mice demonstrated hypertrophy or the lack of it despite high receptor overexpression. To further address the role of the alpha(1)-ARs in cardiac hypertrophy, we analyzed unique transgenic mice that over-express constitutively active mutation (CAM) alpha(1A)-ARs or CAM alpha(1B)-ARs under the regulation of large fragments of their native promoters. These constitutively active receptors are expressed in all tissues that endogenously express their wild-type counterparts as opposed to only myocyte-targeted transgenic mice. In this study, we discovered that CAM alpha(1A)-AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocyte-targeted alpha(1A)-AR mice. We also found cardiac hypertrophy in CAM alpha(1B)-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique alpha(1)-AR-mediated hypertrophic signaling that was AR subtype-specific with CAM alpha(1)A-AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM alpha(1B)-AR mice expressed activated nuclear factor-kappa B (NF-kappa B). These particular hypertrophic signals were blocked when the other AR subtype was coactivated. We also discovered that crossbreeding the two CAM models (double CAM alpha(1A/B)-AR) inhibited the development of hypertrophy and was reversible with single receptor activation, suggesting that coactivation of the receptors can lead to novel antagonistic signal transduction. This was confirmed by demonstrating antagonistic signals that were even lower than normal controls in the double CAM alpha(1A/B)-ARmice for p38, NF-kappa B, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because a alpha(1A/B) double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of alpha(1A)-AR cardiac hypertrophy.

  • 出版日期2013-5