Cardiovascular Research 2007 76(1):5-7; doi:10.1016/j.cardiores.2007.07.011
Copyright © 2007, European Society of Cardiology
Anti-β1AR antibodies in dilated cardiomyopathy: Are these a new class of receptor agonists?
Terence E. Hébert*
Department of Pharmacology and Therapeutics, Faculty of Medicine, 13th floor, Room 1303, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6
*Tel.: +1 514 398 1398; fax: +1 514 398 6690. terence.hebert{at}mcgill.ca
Received 5 July 2007; accepted 18 July 2007
See article by Tutor et al.[9](pages 51–60) in this issue.
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1. Introduction
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Under physiological conditions, the β
1-adrenergic receptor
(β
1AR) is the predominant βAR responsible for inotropic,
chronotropic and lusitropic responses in the myocardium via
the classical Gs/adenylyl cyclase/PKA pathway (reviewed in
[1–3]).
However, during the development of heart failure, sustained
β
1AR signalling may also lead to a number of adverse effects
including cardiomyocyte hypertrophy and eventually apoptosis.
It has become clear in recent years that alterations in the
ERK and other MAP kinase signalling cascades play critical and
complicated roles in the development of cardiac hypertrophy
and the progression towards heart failure
[4]. It is also clear
that β-adrenergic receptors are key regulators of MAP kinase
signalling, especially in the context of heart disease
[5].
In a series of interesting papers, Martin Lohse and his colleagues
have demonstrated a causal role in disease progression for autoimmune
anti-β
1AR antibodies found in patients with dilated cardiomyopathy
(DCM,
[6–8]). In an article in this issue of
Cardiovascular Research, Tutor et al.
[9] demonstrate a novel link between
all of these observations by showing that anti-β
1AR antibodies
from several patients with DCM, but not control sera from healthy
donors or sera from DCM patients that do not produce anti-β
1AR,
can activate the ERK signalling pathway in a manner distinct
from receptor ligands. Their study has significant implications
for basic receptor biology as well as the role of these antibodies
in modulating βAR function in DCM.
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2. Anti-receptor antibodies and ERK signalling
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One of the first surprises in the study was that anti-β
1AR
antibodies from a number of different DCM patients stimulated
ERK1/2 as potently as isoproterenol and with similar kinetics.
The same results were obtained in receptor-transfected HEK 293
cells, the HL-1 cardiomyocyte cell line (which expresses the
receptor endogenously) and in acutely isolated neonatal myocytes.
In all cases, the responses were sensitive to the β
1AR
blocker CGP 20712A. Another interesting finding was that isoproterenol
and the anti-β
1AR antibodies used different signalling
pathways to activate ERK1/2. Although there were some commonalities
in that neither response was pertussis toxin-sensitive and both
were blocked by the PKA inhibitor H-89, indicating a role for
the Gs/adenylyl cyclase/PKA cascade, the response to the anti-β
1AR
antibodies was inhibited by the src antagonist PP2 but not by
mono-dansylcadaverine, a blocker of endocytosis and subsequent
receptor internalization. The converse was true for isoproterenol-mediated
ERK activation.
The most striking observation in the study is that the localization and likely the putative cellular targets for ERK1/2 also differed between isoproterenol- and anti-β1AR antibody-stimulated cells. Isoproterenol stimulation resulted in a predominately cytosolic pattern of phospho-ERK accumulation, while stimulation with the anti-β1AR antibodies led to an accumulation of phospho-ERK in the nucleus [9]. A number of studies have shown that the targets of ERK signalling critically depend on where the ERK is localized physically in the cell [10–13]. Interestingly, dual stimulation led to accumulation of phospho-ERK in both cytosolic and nuclear compartments. It would have been interesting in the case of isoproterenol to see if this was due to the β1AR alone, since isoproterenol also stimulates the β2AR.
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3. Interactions between anti-receptor antibodies and ligands
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The distinct signalling pathways and subcellular localizations
of phospho-ERK engendered by the different means of receptor
activation may alter significantly the outcome of activating
the same populations of receptor. Recent experiments suggest
that G-protein-coupled receptor signalling pathways can be functionally
compartmentalized such that different agonists acting at the
same receptor may have different potencies depending on which
effector pathway is being assayed (see
[14,15] for review).
This "agonist trafficking" or "stimulus trafficking" challenges
the classical pharmacological definition of efficacy, which
posits that agonist potency is independent of effector output.
It has been suggested that receptors can exist in distinct states
that differ in their ability to interact with a particular G-protein.
Thus, agonists can "select" particular receptor/G-protein combinations
that differ in their ability to stimulate particular effectors.
It follows that a spectrum of ligands may be found, some that
are pathway specific and some that target all effector pathways
of a given receptor equally. The results presented by Tutor
et al.
[9] are very important findings as they provide a glimpse
into agonist- or stimulus-directed trafficking in a physiological
context. This notion is brought into even sharper relief by
the observations that co-stimulation with agonist and anti-β
1AR
antibodies revealed a synergism between them when lower doses
were used. In addition, β-blockers such as atenolol or
bisoprolol, which were capable of preventing isoproterenol-mediated
activation of ERK signalling, had no effect on stimulation by
anti-β
1AR antibodies. Thus, the anti-β
1AR antibodies
may be acting as an allosteric agonist
[15]. The authors suggest
that the antibodies may induce conformations of the receptor
that are distinct from those induced by agonists. It would have
been interesting again to study the antagonist effects on dual
stimulation.
One important consideration that this study raises is in the treatment of heart failure in patients with DCM. Specific blockers of β1AR are often used to reduce the effects of increased sympathetic tone, which leads to this hypertrophy and eventually decompensated heart failure [16,17]. β1AR stimulation leads directly to a Gs-mediated apoptosis, and it is perhaps not surprising that these receptors are downregulated during the compensatory phase of the development of heart failure (reviewed in [18]). The authors' data indicate that the anti-β1AR antibodies alter signalling downstream of the receptor in a manner distinct from the natural ligand, and this calls into question the systematic use of β-blockers to treat heart failure. Future therapies may also involve combinations of selected β-blockers with immuno-adsorption of anti-β1AR antibodies in cases where these antibodies are present.
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4. Questions remaining
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This work opens several lines of inquiry that will need to be
pursued in the coming years. First, it would be interesting
to have some of these studies pursued in adult cardiomyocytes,
certainly the most relevant cell type of patients suffering
from DCM and other forms of heart failure where this phenomenon
might be important. Next, it will be critical to identify the
distinct populations of ERK targets activated by agonist, anti-β
1AR
antibodies, or both together during the progression of DCM.
How do agonist and antibody stimulation of ERK differ in the
involvement of G-protein-coupled receptor kinases and β-arrestin?
Do the antibodies recognize and interact with heterodimers of
β
1AR and β
2AR, and are the functional effects distinct
[19,20]? Do the antibodies affect receptor trafficking from
the cell surface, and do they play a role in the downregulation
of β
1AR seen during the development and progression of
heart failure? It will also be interesting to determine the
effects of the antibodies on additional receptor signalling
pathways and on the interactions with other signalling partners
normally recruited in response to agonist. Finally, the use
of antibodies or antibody mimics may allow the development of
new types of receptor ligands useful for both therapeutic purposes
and for generating a better understanding of receptor function
at the molecular level.
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Acknowledgment
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T.E.H. holds a senior scholarship from the Fonds de Recherche
en Santé du Québec.
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References
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1. Introduction
2. Anti-receptor antibodies and...