RT Journal Article
SR Electronic
T1 α<sub>1A</sub>-Adrenergic Receptors Regulate Cardiac Hypertrophy <em>In Vivo </em> Through IL-6 Secretion
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.084483
DO 10.1124/mol.112.084483
A1 Robert S. Papay
A1 Ting Shi
A1 Michael T Piascik
A1 Sathyamangla V. Naga Prasad
A1 Dianne M. Perez
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/02/12/mol.112.084483.abstract
AB The role of α1-adrenergic receptors (AR) in the regulation of cardiac hypertrophy is still unclear, as transgenic mice have demonstrated hypertrophy or the lack of it despite high receptor overexpression. To further address the role of the α1-ARs in cardiac hypertrophy we analyzed unique transgenic mice that overexpress CAM α1A-ARs or CAM α1B-ARs under the regulation of large fragments of their native promoters. These constitutively active receptors are expressed in all tissues that endogenously express their WT 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 the myocyte-targeted α1A-AR mice. We also found cardiac hypertrophy in CAM α1B-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique α1-AR-mediated hypertrophic signaling that was AR subtype-specific with CAM α1A-AR mice secreting ANF and IL-6, while CAM α1B-AR mice expressed activated NF-κB. These particular hypertrophic signals were blocked when the other AR subtype was co-activated. 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 co-activation 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 α1A/B-AR mice for p-38, NF-κB and the IL-6/gp130/STAT3 pathway. As 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.