α_1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion

Abstract

The role of a 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 a 1 -ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) a 1A -ARs or CAM a 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 a 1A -AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocytetargeted a 1A -AR mice. We also found cardiac hypertrophy in CAM a 1B -AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique a 1 -AR-mediated hypertrophic signaling that was AR subtypespecific with CAM a 1A -AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM a 1B -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 a 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 a 1A/B -AR mice for p38, NF-kB, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because a 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 a 1A -AR cardiac hypertrophy.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

“…In the same study, overexpression of a wild-type (WT) a 1 B with the endogenous a 1 B-promoter shows a lesser degree of hypertrophy (Zuscik et al, 2001). More recently, a different result was found in that overexpression of the CAM a 1 B caused hypertrophy, but only in older mice, and hypertrophy was associated with fibrosis (Papay et al, 2013). Furthermore, hypertrophy seen in both the CAM a 1 A and a 1 B mice was not observed when the mice were interbred to derive a systemic CAM a 1 AB transgenic mouse (Papay et al, 2013).…”

“…More recently, a different result was found in that overexpression of the CAM a 1 B caused hypertrophy, but only in older mice, and hypertrophy was associated with fibrosis (Papay et al, 2013). Furthermore, hypertrophy seen in both the CAM a 1 A and a 1 B mice was not observed when the mice were interbred to derive a systemic CAM a 1 AB transgenic mouse (Papay et al, 2013). In contrast with these results, relatively high-level overexpression of the WT a 1 B with the aMyHC promoter (.40-fold) does not induce hypertrophy but results in dilated cardiomyopathy and death (Akhter et al, 1997;Grupp et al, 1998;Iaccarino et al, 2001;Lemire et al, 2001).…”

“…On the other hand, transgenic overexpression of constitutively active mutant (CAM) a 1 A with the endogenous a 1 A-promoter induces cardiac hypertrophy without an effect on systemic blood pressure (Papay et al, 2013).…”

“…Several mechanisms for a 1 -AR-mediated hypertrophic signaling are proposed, and a multitude of signal transducers are implicated (Jensen et al, 2011). Certain molecules, based on frequency in the literature, might be considered essential or "core" molecules required for a 1 -AR-mediated hypertrophic signaling, including PLC (Filtz et al, 2009;Zhang et al, 2013), PKC (a, d, and «, three main isotypes activated by a 1 -ARs) (Henrich and Simpson, 1988;Kariya et al, 1991Kariya et al, , 1993Kariya et al, , 1994Karns et al, 1995;Haworth et al, 2000;Rohde et al, 2000;Braz et al, 2002Braz et al, , 2004Vega et al, 2004;Carnegie et al, 2008), PKD (Haworth et al, 2000;Vega et al, 2004;Harrison et al, 2006;Avkiran et al, 2008;Bossuyt et al, 2008Bossuyt et al, , 2011Carnegie et al, 2008;Liu et al, 2009), ERK (Bueno et al, 2000;Xiao et al, 2001;Barron et al, 2003;O'Connell et al, 2003), and class 2 histone deacetylase (Vega et al, 2004;Backs et al, 2006Backs et al, , 2008 Evidence also exists that transactivation of the EGFR is involved in a 1 -mediated hypertrophy (Morris et al, 2004;Guo et al, 2009;Li et al, 2011;Papay et al, 2013).…”

The alpha1-adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications

“…A recent study compared the cardiovascular phenotype of transgenic mice overexpressing (2 to 8-fold in the heart) CAMs of the α 1a or α 1b -subtype or both together using their native promoters [37]. Transgenic mice overexpressing the α 1a or α 1b -AR CAM displayed cardiac hypertrophy, whereas mice overexpressing both CAMs after crossbreeding did not, thus suggesting some antagonistic signaling interactions when both receptors are co-activated.…”