Cardiovascular Research 2005 65(4):763-765; doi:10.1016/j.cardiores.2005.01.002
Copyright © 2005, European Society of Cardiology
Symbols within words: Have we neglected the AdeNOsine A2 receptor?
Joel S. Karliner
Cardiology Section (111C), Veterans Affairs Medical Center and Department of Medicine University of California, San Francisco CA 94121, USA
joel.karliner{at}med.va.gov
Received 28 December 2004; accepted 4 January 2005
See article by Xu et al. [10] (pages 803–812) in this issue.
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1. Adenosine and cardioprotection in patients: a crossroads?
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Although considerable experimental effort has been expended
during the past two decades in identifying mechanisms of cardioprotection,
little of this work has been of direct benefit to patients.
Thus, Bolli et al. have expressed concern that the field of
myocardial protection is at a crossroads and have emphasized
that there is an urgent need for the extensive experimental
work in this area to be translated into clinically effective
therapy
[1]. The authors of this article, who represented a
Working Group convened by the National Heart, Lung and Blood
Institute, concluded that a Phase III clinical trial of adenosine
be undertaken in patients with acute myocardial infarction
[1].
This recommendation was based on preclinical studies and on
Phase I and II clinical trials of adenosine and related compounds,
which showed promise, but which only studied surrogate markers
or were insufficiently powered to demonstrate definitive clinical
benefit
[2–4]. Thus, accumulating a greater understanding
of the mechanisms of action of adenosine and its cognate receptor
subtypes is both relevant and timely.
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2. Adenosine: a molecule skilled at multi-tasking
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It is well-recognized that adenosine has multiple effects on
the cardiovascular system. Among its many actions, adenosine
enhances coronary blood flow, inhibits adenylyl cyclase activation,
and has direct effects, both positive and negative, on myocardial
inotropic state. Through its effects on conduction tissue, it
modulates heart rate. During myocardial injury, it affects neutrophil
accumulation, reactive oxygen intermediate generation and endothelial
function. These pleiotropic actions, many of which are generally
considered to be cardioprotective, are usually attributed to
activation of adenosine A
1 and A
3 receptors
[5]. Relatively
but not altogether neglected has been the role of adenosine
A
2 receptors. For example, reports in dog models showed that
adenosine A
2 receptor activation reduced reperfusion injury
by inhibiting neutrophil accumulation and coronary endothelial
adherence of these cells
[6], and attenuated reperfusion-induced
apoptotic cell death by modulating expression of Bcl-2 and Bax
proteins
[7]. Other studies in the rabbit showed that adenosine
A
2 receptor agonists improved hemodynamics, reduced creatine
kinase release, and preserved ATP content when these agonists
were given at the time of reperfusion
[8,9].
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3. Insights into mechanisms of adenosine A2 receptor agonism: what's new?
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In this issue of
Cardiovascular Research, Xu et al. have focused
on the ability of adenosine, via the A
2 receptor and a subsequent
series of signaling events, to induce nitric oxide (NO) by downstream
activation of endothelial nitric oxide synthase (eNOS)
[10].
Despite its name, eNOS is constitutively expressed in the particulate
subcellular fraction of cardiac myocytes and is targeted to
caveoli
[11]. The intermediate signaling events elucidated by
the authors include a number of molecules such as PI 3-kinase
and Akt that appear to constitute a pathway used by many G-protein-coupled
agonists that promote cell survival. Their report is the first
to show that adenosine is capable of directly stimulating the
production of NO in cardiac myocytes. Using inhibition experiments,
they also demonstrate that cGMP-dependent protein kinase (PKG)
is involved in the cardioprotective effect of adenosine. Their
data suggest that, by stimulating NO and thereby activating
PKG, the H
2O
2-induced depolarization of the mitochondrial membrane
potential as measured by TRME fluorescence was prevented. These
observations are consistent with a prior publication by Xu et
al. in which it was reported that
S-nitroso-
N-penicillamine
(SNAP)-induced reactive oxygen species generation is mediated
by activation of PKG and subsequent opening of mitochondrial
K
ATP channels, a sequence of events that leads to cardioprotection
[12].
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4. Adenosine A2 receptor agonism: what we don't know
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Like all stimulating work, the paper by Xu et al. provokes a
number of additional questions that can only be answered by
further research. First, the authors used pharmacological concentrations
of adenosine in an in vitro system to obtain their results.
A threshold concentration of adenosine needs to be established
and available selective adenosine A
2 agonists
[6–9] then
tested both in vivo and in vitro to determine their effects
on the measures reported by Xu and colleagues. Whether the data
will hold across species also needs to be studied, but the benefit
afforded by adenosine A
2 agonists in dogs and rabbits is encouraging
[6–9]. The data of Xu et al. are additionally intriguing
because NO at low concentrations, such as are likely to be generated
by activation of eNOS, is cytoprotective
[13]. Whether segments
of the MAP kinase cascade other than ERK
[12], such as JNK 1/2
[13], are involved in NO-induced cytoprotection by activation
of adenosine A
2 receptors should be ascertained. NO generated
within mitochondria by a neural form of NOS may be directly
involved in the function of these organelles; this possibility
has not been explored using selective adenosine A
2 agonists.
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5. Group therapy
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As the authors indicate, PKC and mitochondrial K
ATP channels
are important in the protective effects of adenosine A
1 receptor
activation, but their roles in adenosine A
2 receptor activation
remain unknown. It is well recognized that PKC
is a critical
signaling component of ischemic and of several forms of pharmacologic
preconditioning. In this connection, Otani et al. recently reported
that adenosine, diazoxide and the NO donor SNAP each activated
PKC
, but this PKC isoform was inactivated after washout
[14].
In contrast, after triple pharmacologic preconditioning with
these agents in combination, PKC
remained activated and persistent
cardioprotection ensued. This cardioprotective effect was abolished
by treatment prior to the index ischemia with the PKC inhibitor
chelerythrine
[14]. These observations suggest that a single
agent is likely to be ineffective in achieving optimal myocardial
salvage, and that testing one drug alone, as recommended by
the NHLIBI Working Group
[1], may be insufficient. Rather a
"cocktail" of agents may be better suited for cardioprotection,
much as is done under other circumstances by our oncology colleagues.
Such an approach is underscored by recent data indicating that
cardioprotection is induced by both the physical and functional
coupling of a signaling module consisting of PKC
, Akt and eNOS
[15]. All three components of this module can be activated by
adenosine A
2 receptor agonists in combination with one or more
other agents as described above. Thus, not only does the word
adeNOsine resemble a signaling module, but, based on the data
of Xu et al.
[10], the symbol NO in the word may be real.
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References
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