Joseph R Burgoyne

Oleksandra Prysyazhna

Philip Eaton

BMC Pharmacology and Toxicology

Springer - Publisher Connector

Tadalafil protects from doxorubicin-induced heart failure by attenuating PKG Iα disulfide dimerisation

MEETING ABSTRACT Open Access
Tadalafil protects from doxorubicin-induced heart
failure by attenuating PKG Ia disulfide dimerisation
Oleksandra Prysyazhna*, Joseph R Burgoyne, Philip Eaton
From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications
Trier, Germany. 19-21 June 2015
Background
Phosphodiesterase (PDE) 5 inhibitors, which prevent
cGMP degradation and therefore elevate its level in the
heart, have been shown to protect the myocardium in
several animal models of heart failure and in human
trials. cGMP binding to protein kinase G (PKG) results
in its classical activation and also prevents disulfide
dimerisation-dependent activation of this kinase. Doxor-
ubicin (DOX) is an anti-cancer drug which commonly
causes cardiomyopathy, the pathogenesis of which is
associated with increased oxidant production and apop-
tosis. We hypothesised that oxidative activation of PKG
Ia may mediate DOX-induced cardiotoxicity, and PDE5
inhibitors may be protective because they elevate cGMP
which then limits the oxidative activation.
Methods
To test the hypothesis that PKG Ia disulfide dimerisation
is involved in the development of DOX-induced cardio-
myopathy, we used PKG Ia knock-in (KI) mice that
express C42S kinase that cannot be oxidant-activated.
DOX (15mg/kg) or saline was injected intraperitoneally to
wild type (WT) and KI littermate male mice and hearts
were analysed 5 days later. In separate experiments mice
were co-treated with DOX and tadalafil (1mg/kg 30 min
before DOX and then daily). Hearts were assessed by
echocardiography, and then tissues were histologically
assessed for apoptosis by quantitative TUNEL staining.
Proteins involved in the pro-survival signalling and apop-
tosis were also analysed by immunoblotting analyses of
these tissues.
Results
Doxorubicin treatment caused loss of myocardial tissue
and depression of left ventricular function, reduced pro-
survival signaling and increased apoptosis in WT mice.
Thus in the WT exposed to DOX ejection fraction
decreased by 17%, apoptotic nuclei increased 7-fold, the
BCL2/Bax ratio decreased, and the phosphorylation status
of each of ERK, AKT and GSK3b significantly decreased.
In contrast, KI mice were markedly resistant to this dys-
function. In WT mice, co-administration of tadalafil with
doxorubicin reduced PKG Ia oxidation caused by doxoru-
bicin, and also protected against cardiac injury and loss of
function. KI mice were again resistant to doxorubicin car-
diotoxicity, and therefore tadalafil did not cause any addi-
tional protection. Doxorubicin treatment resulted in a
decrease of RhoA (Ser188) phosphorylation in WT, but
not KI mice, stimulating its GTPase activity to activate
ROCK. These pro-apoptotic events were attenuated in
WTs co-administered with tadalafil.
Conclusion
These data suggest that PKG Ia disulfide formation trans-
duces oxidant signals that arise in the heart during DOX
chemotherapy into a pro-apoptotic signal, leading to cardi-
omyopathy. The PDE5 inhibitor tadalafil abrogates this
maladaptive signaling through cGMP elevation, which
binds the kinase to limit its oxidation. Consistent with
this, mice lacking the C42 redox-sensor in PKG Ia are
therefore protected from heart cell apoptosis and injury
otherwise induced by DOX.
Published: 2 September 2015
doi:10.1186/2050-6511-16-S1-A75
Cite this article as: Prysyazhna et al.: Tadalafil protects from doxorubicin-
induced heart failure by attenuating PKG Ia disulfide dimerisation. BMC
Pharmacology and Toxicology 2015 16(Suppl 1):A75.
* Correspondence: oleksandra.prysyazhna@kcl.ac.uk
King's College London, London, SE1 7EH, UK
Prysyazhna et al. BMC Pharmacology and Toxicology 2015, 16(Suppl 1):A75
http://www.biomedcentral.com/2050-6511/16/S1/A75
© 2015 Prysyazhna et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


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Tadalafil protects from doxorubicin-induced heart failure by attenuating PKG Iα disulfide dimerisation

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