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, Alison C. Cave

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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 A(1)-receptor agonists antagonize beta-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. 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 A(1) 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. These data support the hypothesis that sustained cTnI phosphorylation underlies the contractile dysfunction seen in sepsis.
Original languageEnglish
Pages (from-to)67 - 76
Number of pages10
JournalCardiovascular Research
Issue number1
Publication statusPublished - Apr 2009


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