Complement and sepsis-induced heart dysfunction

Abstract

It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after “recovery” from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis. The molecular basis for cardiac dysfunctions is linked to generation of C5a and its interaction with C5a receptors present on surfaces of cardiomyocytes (CMs). It is established that C5a interactions with C5a receptors leads to significant reductions involving faulty contractility and relaxation in CMs. In addition, C5a interactions with C5a receptors or CMs results in reductions in Na+/K+-ATPase in CMs. This ATPase is essential for intact action potentials in CMs. The enzymatic activity and protein for this ATPase were strikingly reduced in CMs during sepsis by unknown mechanisms. In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca2+]i in CMs: sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) and Na+/Ca2+ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.

Complement‐induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction

“…Likewise, CMs isolated from CLP hearts showed increased levels of C5aR1 (8). These data suggest that C5a plays an important role in the development of harmful outcomes of sepsis, especially involving the heart, through its receptors (C5aR1 and ‐2) on CMs (9).…”

Complement Activation and Organ Damage After Trauma—Differential Immune Response Based on Surgical Treatment Strategy

“…During the inflammatory condition of CLP-sepsis, C5a-C5aR2 interactions were shown to induce excessive amount of cytosolic ROS and [Ca 2+ i ] in CMs. Further, the absence of the C5aR2 improves heart function in CLP mice (28,58). Therefore, the here shown posttraumatic downregulation of the C5aR2 expression in the heart tissue might even be protective for the heart function during complement activation.…”

C5a anaphylatoxin and its role in critical illness‐induced organ dysfunction

“…C5a induces cardiac dysfunction in multiple rodent models, with defects being detectable by echocardiography in as little as 8 hours . The roles of mitogen activated protein kinases, action potential disturbances and the inflammasome have only more recently been elucidated in subsequent studies by the same group . With respect to the endothelium, C5a stimulates tissue factor and adhesion molecule expression with resulting disruption of the endothelial glycocalyx, leading to further DAMP release into the circulation .…”

“…| 5 of 11 kinases, action potential disturbances and the inflammasome have only more recently been elucidated in subsequent studies by the same group. [106][107][108] With respect to the endothelium, C5a stimulates tissue factor and adhesion molecule expression with resulting disruption of the endothelial glycocalyx, leading to further DAMP release into the circulation. 84,90,109 In systemic lupus erythematosus models, C5a has been shown to induce apoptosis and reduce endothelial integrity.…”