An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction.
Defective cardiac function during sepsis has been referred to as "cardiomyopathy of sepsis." It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a-C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance.
Niederbichler
Andreas D
AD
Department of Surgery, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Hoesel
Laszlo M
LM
Westfall
Margaret V
MV
Gao
Hongwei
H
Ipaktchi
Kyros R
KR
Sun
Lei
L
Zetoune
Firas S
FS
Su
Grace L
GL
Arbabi
Saman
S
Sarma
J Vidya
JV
Wang
Stewart C
SC
Hemmila
Mark R
MR
Ward
Peter A
PA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D015936:Complement C5a / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000502:physiology; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology
D000906:Antibodies; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a