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

Abstract

AimsSepsis-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 resultsCardiomyocytes 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 (B56α) 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.ConclusionThese data support the hypothesis that sustained cTnI phosphorylation underlies the contractile dysfunction seen in sepsis.

Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

“…Hence, there seems to be a causal link between higher expression of PP2A C -B56␣, hypophosphorylation of myofilament proteins, and increased Ca 2ϩ sensitivity and contractile force. This is also supported by the fact that, on the other hand, an increased cTnI phosphorylation at Ser 23/24 and a decrease in myofilament Ca 2ϩ sensitivity in LPS-induced septic hearts was paralleled by a reduction in the expression of PP2A C -B56␣, resulting in an overall decreased PP2A activity (17). Taken together, these studies support the hypothesis that B56␣ is a crucial modulator of cardiac Ca 2ϩ sensitivity and contractility by influencing the PP2A-dependent dephosphorylation of regulatory myofilament proteins.…”

“…Analysis of myocardial fractions revealed that B56␣ was decreased in the myofilament fraction and increased in the cytosol after ␤-adrenergic stimulation by isoproterenol (ISO) (16). These dynamic changes in PP2A-B56␣ targeting may contribute to neurohumoral regulation of cardiac performance under physiological conditions and in the diseased heart, as demonstrated for sepsis-associated cardiac dysfunction (17).…”

Caspase-dependent protein phosphatase 2A activation contributes to endotoxin-induced cardiomyocyte contractile dysfunction*

“…Similarly, we could not detect calmodulin kinase II cleavage in both in vivo and in vitro experiment settings. Implication of phosphatases in the development of sepsis-triggered cardiovascular dysfunction remains controversial (25,26). Here, we showed that PP2A activity is increased in SR vesicles isolated from endotoxin-treated rat hearts.…”

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

“…14 Previous study proved that LPS treatment represses PP2Ac expression and activity in myocardial cells. 15 Considering the tumor suppressive role of PP2A, we speculated that the inflammation-triggered PP2A inhibition participates in the inflammation-driven cancer progression.…”