α1A-Adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion

The role of a1-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 a1-ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) α1A-ARs or CAM a1B-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 α1A-AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocytetargeted α1A-AR mice. We also found cardiac hypertrophy in CAM a1B-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique a1-AR-mediated hypertrophic signaling that was AR subtypespecific with CAM α1A-AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM a1B-AR mice expressed activated nuclear factor-kB (NF-kB). These particular hypertrophic signals were blocked when the other AR subtype was coactivated. We also discovered that crossbreeding the two CAM models (double CAM α1A/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 CAMα1A/B-ARmice for p38, NF-kB, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because α1A/B double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of α1A-AR cardiac hypertrophy.