ORIGINAL ARTICLES:
Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia
Marshall et al. (1 April 2009)
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Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia
Reply to letter by Siracusano & Girasole |
23 April 2009 |
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Melanie Marshall,
Post-Doctoral Research Assistant
Dept of Cardiology, King's College London, 125, Coldharbour Lane, London SE5 9NU,
Jonathon C. Kentish
Send e-letter to journal:
Re: Reply to letter by Siracusano & Girasole
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We would like to thank Siracusano & Girasole (1) for their
interest in our paper (2). We agree that it would be very interesting to
examine PP2A activity in another model of sepsis such as the cecal
ligation puncture (CLP) model. However, the endotoxin-induced model of
sepsis is a well-established and useful model that has been employed
extensively in sepsis research (3-5). We used this model in our study as
it is a very robust model of sepsis-associated cardiac dysfunction.
Furthermore, we were particularly interested in the hypodynamic stage of
sepsis because, in the experimental setting, many drugs appear to reduce
myocardial dysfunction when given as a pre-treatment, but few seem to have
a significant impact when sepsis is already well developed. Our study
shows one way in which endotoxaemia-induced myocardial dysfunction can be
reversed by drug treatment several hours after the onset of sepsis.
Nevertheless, we agree that the pathophysiology of sepsis is complex and
translation of the results from any animal model of sepsis (whether
endotoxin- or CLP-induced) to humans should always be undertaken with
caution.
1) Luca Siracusano, & V. Girasole: PP2A activity in sepsis and the
importance of the experimental model. Cardiovasc Res. 2009; E-letter from 30 March. 2) Marshall M,
Anilkumar N, Layland J, Walker SJ, Kentish JC, Shah AM, Cave AC: Protein
phosphatase 2A contributes to the cardiac dysfunction induced by
endotoxemia. Cardiovasc Res. 2009; 82:67-76. 3) Aoshiba K, Onizawa S,
Tsuji T, Nagai A: Therapeutic effects of erythropoietin in murine models
of endotoxin shock. Crit. Care Med. 2009; 37(3): 889-98. 4) Tsai WH,
Cheng PY, Lee YM, Jiau SS, Wu ES, Yen MH: Anti-inflammatory effects of LK-
3 on LPS-induced sepsis in rats. Chin J. Physiol. 2008; 51(5): 291-300. 5)
Nacira S, Meziani F, Dessebe O, Cattan V, Collins S, Montemont C, Gibot S,
Asfar P, Ramaoson A, Regnault V, Slama M, Lecompte T, Lacolley P, Levy B:
Activated protein C improves lipopolysaccharide-induced cardiovascular
dysfunction by decreasing tissular inflammation and oxidative stress.
Crit. Care Med. 2009 37(1); 246-255.
Conflict of Interest:
None declared |
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Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia
PP2A activity in sepsis and the importance of the experimental model |
30 March 2009 |
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Luca Siracusano,
associate professor
Policlinico of Messina via Consolare Valeria 98121 Messina,
V. Girasole
Send e-letter to journal:
Re: PP2A activity in sepsis and the importance of the experimental model
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We read with great interest the article by Marshall et al (1)
underlining the role of the Protein Phosphatase 2A (PP2A) and of the
balance between kinases and phosphatases in the phosphorylation of
cardiac Troponin I (cTnI) at Ser 23\24 leading to the reduced contractile
function observed in sepsis.
The pathogenesis of the myocardial dysfunction in sepsis is not
definitively explained even though several concomitant causes of the
contractile alteration have been recognized: along with the increased
phosphorylation of cTnI and the consequent reduction in contractile
efficiency, the increase in TNFalpha and other proinflammatory ILs, the
downregulation of beta receptors in the later phases of sepsis,
myocardiocytes death by apoptosis, the excess of nitric oxide systemic
and\or in some critical cell compartments (2-3).
However the choice of the model used in this study may give rise to
some doubt.
It is well known that the degree of cTnI phosphorylation at Ser
23\24, the related calcium sensitivity of myocardiocytes and the beta
adrenergic function have a different behaviour in the early hyperdynamic
and the late hypodynamic phase of the sepsis with an initial increase
followed by a reduction (4); also, the calcium content of the sarcoplasmic
reticulum undergoes modifications during sepsis showing a reduction only
in the hypodynamic phase (5).
In the experimental model of sepsis elicited by endotoxin
administration, in contrast to the cecal ligation and puncture(CLP)
model, there is only the presence of a hypodynamic phase (6), making
difficult the translation of the important data obtained in this study to
the setting of human sepsis, characterized by a biphasic course.
We think it would be very intriguing, in future studies, to control
the course of the PP2A activity in a CLP model of sepsis.
References.
1)Marshall M, Anilkumar N, Layland J, Walker SJ, Kentish JC, Shah AM,
Cave AC: Protein phosphatase 2A contributes to the cardiac dysfunction
induced by endotoxemia. Cardiovasc Res. 2009; 82:67-76.
2)Fernandes CJ Jr, Akamine N, Knobel E: Myocardial depression in sepsis.
Shock. 2008;30 Suppl 1:14-7.
3) Flierl MA, Rittirsch D, Huber-Lang MS, Sarma JV, Ward PA.: Molecular
Events in the Cardiomyopathy of Sepsis. Mol Med 2008 ; 14:327-36.
4)Wu LL, Tang C, Liu MS: Altered phosphorylation and calcium sensitivity
of cardiac myofibrillar proteins during sepsis. Am J Physiol Regul Integr
Comp Physiol. 2001 Aug;281:R408-16
5)Dong LW, Wu LL, Ji Y, Liu MS. Impairment of the ryanodine-sensitive
calcium release channels in the cardiac sarcoplasmic reticulum and its
underlying mechanism during the hypodynamic phase of sepsis. Shock. 2001
Jul;16(1):33-9.
6)Esmon CT: Why do animal models (sometimes) fail to mimic human sepsis?
Crit Care Med. 2004 May;32(5 Suppl):S219-22.
Conflict of Interest:
None declared |
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