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Cardiovascular Research Advance Access originally published online on February 15, 2008
Cardiovascular Research 2008 78(1):5-7; doi:10.1093/cvr/cvn042
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Novel signalling cascade for cardiac hypertrophy activation by uncoupling and internalization of β1-adrenoceptors

Masao Endoh

Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan

* Corresponding author. Tel: +81 23 628 5234; fax: +81 236 28 5235. E-mail address: mendou{at}med.id.yamagata-u.ac.jp

This editorial refers to ‘Endocytosis machinery is required for b1-adrenergic receptor-induced hypertrophy in neonatal rat cardiac myocytes’ by Carmine Morisco et al.,11 pp. 36–44, this issue.

The immediate adaptation of cardiac pump function to haemodynamic stress is achieved by cardiac functional response, such as an increase in heart rate and cardiac contractility regulated through the Frank-Starling mechanism, the force-frequency relationship and adrenergic nerve stimulation. When the haemodynamic stress continues, cardiac hypertrophy develops first as the adaptive response of the myocardium that progresses to pathological (maladaptive) hypertrophy associated with fibrosis and apoptosis, and ultimately to heart failure. Maladaptive cardiac hypertrophy generally predisposes to heart failure and is an important risk factor for an increase in death of patients with heart failure, and therefore the signalling processes responsible for the development of cardiac hypertrophy have been and will be an important research target for therapies based on an understanding of the pathophysiology and development of heart failure.

During the course of cardiac hypertrophy caused by long-lasting pressure and volume overload, and after myocardial infarction, various neurohumoral factors, including catecholamines, angiotensin II (Ang II), endothelin-1 (ET-1), and cytokines, are released into the circulation to advance and/or modulate the course of cardiac hypertrophy.1,2 Activation of various protein kinases is involved in the induction of cardiac hypertrophy.3 For example, membrane receptors of Ang II (AT1 receptor), ET-1 and phenylephrine (PE; {alpha}1-adrenoceptor: {alpha}1-AR) belong to the same family and are coupled to heterotrimeric GTP binding proteins, Gq/11, resulting in the generation of 1,2-diacylglycerol (DAG) which activates protein kinase C and leads to cardiac hypertrophy. Overexpression of DAG kinase {zeta}, which converts DAG to inactive metabolites, suppresses the hypertrophy induced by activation of this family of receptors.4,5 However, the pathophysiological relevance of the hypertrophy induced by these receptor agonists is quite different. While {alpha}-AR stimulation induces adaptive physiological hypertrophy6,7 and prevents the maladaptive cardiac response,8,9 Ang II and ET-1 lead to pathological hypertrophy predisposing to heart failure. The additional signalling process activated by Ang II, which is independent of Gq activation, has been shown to contribute to the difference.10 Thus, Ang II is a main humoral factor leading to pathological cardiac hypertrophy, fibrosis and apoptosis, inhibition of which constitutes the therapeutic basis for the clinical effectiveness of angiotensin converting enzyme (ACE) inhibitors and Ang II AT1 receptor antagonists in the treatment of cardiac hypertrophy and heart failure.

β-Adrenoceptor (β-AR) stimulation also promotes cardiac hypertrophy through a signalling process different from {alpha}-AR stimulation, Ang II, and ET-1. In this issue of Cardiovascular Research, Morisco et al.11 investigated the relation of β–AR endocytosis and cardiac cell hypertrophy during continuous stimulation induced by the non-selective β-AR agonist isoproterenol (ISO) in cultured neonatal rat cardiac myocytes. β-AR-mediated cardiac hypertrophy is primarily due to activation of β1-AR.11,12 Interestingly, the inhibition of individual steps of the signalling cascade involved in β1-AR endocytosis—e.g. by the selective β1-AR blocker betaxolol, β-AR kinase (βARK) inhibition by βARK-CK, dominant negative (DN) β-arrestin 1, DN Src and Src inhibitor PP1, and the endocytosis inhibition by concanavalin A and DN dynamin—all inhibited β–AR-mediated cardiac cell hypertrophy and atrial natriuretic factor transcription. These observations strongly suggest that signalling for activation of endocytosis machinery is responsible for cardiac hypertrophy induced by β1-AR. β1-ARs are downregulated during the course of chronic congestive heart failure in experimental animals and patients, which has been postulated to be an important process to shut out the endogenous signal process by catecholamines to protect the heart from over-production of cyclic AMP and Ca2+ overload.1 The findings by Morisco et al.11 imply that β1-AR internalization is involved in the activation of hypertrophic signalling pathways, indicating that the endocytosis machinery plays diverse roles in cardiac regulation.

An outline of the potential signalling pathway leading to β1-AR-mediated cardiac hypertrophy is as follows (see Figure 6 in Morisco et al.11): β-AR stimulation is coupled to activation of Gs protein to generate Gs{alpha} and Gβ{gamma} subunits. As well established, Gs{alpha} is responsible for activation of adenylyl cyclase, resulting in accumulation of cyclic AMP and activation of PKA. This brings about a prominent elevation of intracellular [Ca2+], readily causing intracellular Ca2+ overload and ultimately leading to cardiac hypertrophy and heart failure in association with myocardial cell injury and death (apoptosis and/or necrosis). The signalling pathway for receptor endocytosis is triggered by Gβ{gamma} via activation of βARK 1 to phosphorylate β1-AR, which becomes sterically inactivated (uncoupled from Gs protein activation) by binding to β-arrestin 1. This process leads to activation of Src to result in phosphorylation of proteins involved in clathrin-mediated endocytosis such as dynamin and clathrin heavy chain. Simultaneously, Src activates Akt by phosphorylation, probably through involvement of the activation of phosphoinositide 3-kinase (PI3K) and/or Ca2+/calmodulin kinase II, which constitutes the common hypertrophic pathway shared by various types of G protein-coupled receptors.

It should be noted that the experiments by Morisco et al.11 were carried out in neonatal rat cultured cardiac cells. Therefore, how the regulation is modulated in adult in vivo heart failure awaits further study. In their experiments, the ISO-induced cyclic AMP accumulation was unaffected by inhibition of receptor downregulation probably because of very high concentration of ISO in the study, as generally employed in the experiments for induction of receptor endocytosis. The {alpha}-AR agonist PE induced effects similar to those of β1-AR stimulation, but to a moderate extent, which were inhibited by concanavalin A.11 The possibility, however, was not excluded in these experiments that the effects of PE were due to activation of weak β1-AR stimulation induced by PE. Comparison of concentration dependence and time dependence of functional alteration, β1-AR internalization, and development of cardiac cell hypertrophy will be necessary to establish the pathophysiological and therapeutic relevance of activation of endocytosis machinery.

Involvement of βARK1 in cardiac hypertrophy and heart failure has been shown in various models of cardiovascular diseases. In a mouse model of hypertrophic cardiomyopathy, cardiac expression of a peptide inhibitor of βARK1 not only prevented systolic dysfunction and increased exercise tolerance but also decreased cardiac remodelling and hypertrophic gene expression.13 In a mouse model of chronic pressure overload-induced heart failure, inhibition of βARK1 by expression of βARK-CT suppressed cardiac deterioration and preserved the ISO-stimulated adenylyl cyclase activity and normal β-AR densities.14 These findings imply that it is highly likely that the endocytosis machinery, including the downstream factors β-arrestin 1 and Src, and clathrin-mediated endocytosis itself, could be playing a crucial role in determining the progression to maladaptive cardiac hypertrophy and contractile dysfunction in congestive heart failure, and would be good target for pharmacological therapy of maladaptive hypertrophy. On the other hand, there is a report showing that G protein-coupled receptor internalization signalling, including Gβ{gamma}, βARK, and subsequent PI3K activation, is required for cardioprotection in ischaemic preconditioning,15 an indication that the involvement of receptor endocytosis in cardiovascular diseases is complex and an important target of future study.

β-AR- and Ang II-induced cardiac hypertrophy share the common pathway involving PI3K/Akt/NF{kappa}B in vivo.16 On the other hand, it has recently been described that not all hypertrophy is created equal.2 A number of neurohumoral factors and receptors, including cytokines, neurotrophin-3,17 eNOS,18 ANP,19 aldosterone20 and PPAR{alpha},21 in addition to well-established Gq-coupled signalling,22 contribute to the development of different types of cardiac hypertrophy by interacting with each other in patients with cardiac hypertrophy and heart failure. Reflecting involvement of these multiple regulatory pathways, β-AR signalling in human cardiac hypertrophy depends on the underlying disease.23 Despite these complexities, the fact that β-AR blockers elicit additional beneficial effects on survival of patients with heart failure treated with ACE inhibitors24 indicates that modulation of processes upstream to the common hypertrophic signalling pathway is capable of raising therapeutic effectiveness of heart failure pharmacotherapy. In this context, the findings by Morisco et al.11 on the role of endocytosis machinery in the development of cardiac hypertrophy indicate a novel significance of chronic receptor stimulation and will cause a paradigm shift of the pathophysiological and therapeutic relevance of receptor internalization.


   Notes
 
The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology. Back


   References
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 References
 

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Endocytosis machinery is required for β1-adrenergic receptor-induced hypertrophy in neonatal rat cardiac myocytes
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