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 on 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+-ATPase2 (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.