Complement and sepsis-induced heart dysfunction

被引:43
作者
Fattahi, Fatemeh [1 ]
Ward, Peter A. [1 ]
机构
[1] Univ Michigan, Sch Med, Dept Pathol, 1301 Catherine St, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
Complement C5a; C5aR1; C5aR2 (GPR77); Na+/K+-ATPase; Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2); Na+/Ca2+ exchanger (NCX); CARDIAC SARCOPLASMIC-RETICULUM; RESPIRATORY-DISTRESS-SYNDROME; INTENSIVE-CARE-UNIT; SEPTIC SHOCK; EXTRACELLULAR HISTONES; CRITICALLY-ILL; MYOCARDIAL DYSFUNCTION; INTRACELLULAR CALCIUM; UNDERLYING MECHANISM; FLUID RESUSCITATION;
D O I
10.1016/j.molimm.2016.11.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ca(2+-)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. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码:57 / 64
页数:8
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