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Cardiovascular Research Advance Access first published online on February 6, 2009
This version [Corrected Proof] published online on February 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp037
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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.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia

Melanie Marshall*, Narayana Anilkumar, Joanne Layland, Simon J. Walker, Jonathan C. Kentish, Ajay M. Shah and Alison C. Cave

Cardiovascular Division, Department of Cardiology, King's College London, James Black Centre, London SE5 9NU, UK

* Corresponding author. Tel: +44 20 7848 5359; fax: +44 20 7848 5193. E-mail address: melanie.marshall{at}kcl.ac.uk

Aims: Sepsis-associated cardiac dysfunction represents an intrinsic impairment of cardiomyocyte function due in part to a decrease in myofilament Ca2+ sensitivity associated with a sustained increase in cardiac troponin I (cTnI) phosphorylation at Ser23/24. Dephosphorylation of cTnI is under regulatory control. Thus, muscarinic and adenosine A1-receptor agonists antagonize β-adrenergic stimulation via activation of protein phosphatase 2A (PP2A). The aim of this study was to determine whether modulation of PP2A and thus cTnI phosphorylation could improve sepsis-induced contractile dysfunction.

Methods and results: Cardiomyocytes were isolated from control or septic mice 16–18 h after an injection of vehicle or lipopolysaccharide (LPS; 9 mg/kg ip) respectively. Protein expression and phosphatase activity were determined in homogenates of control and septic hearts. Our data showed that LPS significantly increased cTnI phosphorylation at Ser23/24 in cardiomyocytes and reduced contraction amplitude without affecting Ca2+-transients. Treatment of cardiomyocytes with the A1 agonist cyclopentyladenosine (CPA) or the protein kinase A inhibitor H89 significantly attenuated the LPS-induced contractile dysfunction without effect on Ca2+-transients. Co-treatment with CPA and H89 completely reversed the contractile dysfunction. Increased cTnI phosphorylation in septic hearts was associated with a significant reduction in the protein expression of both the catalytic and regulatory subunits (B56{alpha}) of PP2A and a decrease in PP2A activity. CPA treatment of septic hearts increased PP2A activity. An increase in the protein expression of demethylated PP2A and a decrease in the PP2A-methyltransferase (PPMT; the methyltransferase that catalyses this reaction) were also observed.

Conclusion: These data support the hypothesis that sustained cTnI phosphorylation underlies the contractile dysfunction seen in sepsis.

KEYWORDS Troponin I; Cardiomyocytes; Myofilaments; Phosphorylation; Protein phosphatase 2A

Time for primary review: 23 days


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PP2A activity in sepsis and the importance of the experimental model
Luca Siracusano, et al.
Cardiovascular Research, 30 Mar 2009 [Full text]
Reply to letter by Siracusano & Girasole
Melanie Marshall, et al.
Cardiovascular Research, 23 Apr 2009 [Full text]

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