Activated protein C and inflammation in human myocardium after heart surgery

Petäjä, Jari; Pesonen, Eero; Fernández, José A.; Griffin, John H.; Repo, Heikki; Jansson, Sten‐Erik; Vento, Antti; Rämö, O. J.

doi:10.1002/ajh.1110

Cited by 17 publications

(7 citation statements)

References 10 publications

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“…In experimental I/R of the liver (26), spinal cord (27), and kidney (28), exogenous APC attenuated I/R injury by decreasing the tissue content of proinflammatory cytokines tumor necrosis factor-␣ and interleukin-8, and by decreasing neutrophil accumulation into the reperfused tissue. In accordance with these experimental findings, we have previously reported a negative correlation between protein C activation and myocardial neutrophil accumulation after reperfusion in clinical cardiopulmonary bypass (11). It can be speculated that, in our patients, APC was, at least partly, used within the liver graft to modulate inflammatory response during reperfusion.…”

Section: Discussionsupporting

confidence: 92%

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Activation of protein C during reperfusion in clinical liver transplantation

Ilmakunnas

Petäjä²,

Höckerstedt³

et al. 2003

Transplantation

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Despite protein C deficiency, patients with liver insufficiency are able to maintain normal APC levels. During reperfusion, protein C consumption occurs in the liver without concomitant hepatic release of APC, indicating a shortage of APC in the reperfused liver. The process consuming protein C and APC may be related to the simultaneous ongoing neutrophil and monocyte activation within the liver graft, indicating a regulatory role for APC in inflammation.

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Section: Discussionsupporting

confidence: 92%

“…In vivo, APC reduces mortality in animal models of sepsis (7)(8)(9) and in clinical septicemia (10). During reperfusion in human cardiac surgery, protein C activation is associated with reduced myocardial sequestration of neutrophils (11) and favorable hemodynamic recovery (12).…”

mentioning

confidence: 99%

Activation of protein C during reperfusion in clinical liver transplantation

Ilmakunnas

Petäjä²,

Höckerstedt³

et al. 2003

Transplantation

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“…This suggests a link in vivo between APC and neutrophil function and points toward future in vivo studies. Of potential relevance, a previous study observed that in heart surgery patients, a negative correlation between neutrophil MPO activity in the myocardium and generation of APC was observed post surgery (72).…”

Section: Discussionmentioning

confidence: 92%

Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo

Healy

Puy

Fernández

et al. 2017

Journal of Biological Chemistry

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Activated protein C (APC) is a multifunctional serine protease with anticoagulant, cytoprotective, and anti-inflammatory activities. In addition to the cytoprotective effects of APC on endothelial cells, podocytes, and neurons, APC cleaves and detoxifies extracellular histones, a major component of neutrophil extracellular traps (NETs). NETs promote pathogen clearance but also can lead to thrombosis; the pathways that negatively regulate NETosis are largely unknown. Thus, we studied whether APC is capable of directly inhibiting NETosis via receptor-mediated cell signaling mechanisms. Here, by quantifying extracellular DNA or myeloperoxidase, we demonstrate that APC binds human leukocytes and prevents activated platelet supernatant or phorbol 12-myristate 13-acetate (PMA) from inducing NETosis. Of note, APC proteolytic activity was required for inhibiting NETosis. Moreover, antibodies against the neutrophil receptors endothelial protein C receptor (EPCR), protease-activated receptor 3 (PAR3), and macrophage-1 antigen (Mac-1) blocked APC inhibition of NETosis. Select mutations in the Gla and protease domains of recombinant APC caused a loss of NETosis. Interestingly, pretreatment of neutrophils with APC prior to induction of NETosis inhibited platelet adhesion to NETs. Lastly, in a nonhuman primate model of -induced sepsis, pretreatment of animals with APC abrogated release of myeloperoxidase from neutrophils, a marker of neutrophil activation. These findings suggest that the anti-inflammatory function of APC at therapeutic concentrations may include the inhibition of NETosis in an EPCR-, PAR3-, and Mac-1-dependent manner, providing additional mechanistic insight into the diverse functions of neutrophils and APC in disease states including sepsis.

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“…APC decreases neutrophil accumulation in the postischemic tissue (36, 46 -48), an effect likely mediated through cell adhesion, as APC reduces intercellular adhesion molecule-1 expression on the endothelium and tissue accumulation of CD11b positive neutrophils in experimental I/R injury (37). We have previously shown that postischemic protein C activation is associated with decreased neutrophil tissue sequestration after human cardiac surgery, suggesting that protein C pathway may exert some of its anti-inflammatory actions by preventing phagocyte emigration from circulation rather than by inhibiting their intravascular activation (49). Indeed, current results suggest that, in clinical I/R-injury, anti-inflammatory properties of protein C pathway may originate from decreased adhesive potential due to decreased CD11b expression.…”

Section: Discussionmentioning

confidence: 96%

Graft protein C entrapment is associated with reduced phagocyte activation during reperfusion in human liver transplantation

Ilmakunnas

Pesonen²,

Höckerstedt³

et al. 2006

Critical Care Medicine

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Protein C entrapment occurs immediately during reperfusion in the graft without concomitant activated protein C release, suggesting a shortage of activated protein C in the reperfused graft. The ongoing inflammatory response during reperfusion may lead to protein C and activated protein C utilization within the graft. Indeed, hepatic protein C entrapment is associated with reduced hepatic phagocyte activation, suggesting a regulatory role for protein C pathway in hepatic reperfusion in human liver transplantation.

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Activated protein C and inflammation in human myocardium after heart surgery

Cited by 17 publications

References 10 publications

Activation of protein C during reperfusion in clinical liver transplantation

Activation of protein C during reperfusion in clinical liver transplantation

Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo

Graft protein C entrapment is associated with reduced phagocyte activation during reperfusion in human liver transplantation

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