An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction

Abstract

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.

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

“…Recently, we demonstrated the expression of the C5a receptor, C5aR, on isolated rat CMs. We showed that experimental sepsis resulted in the increased expression of C5aR on CMs in a time-dependent manner (14). The interaction of C5a with C5aR resulted in an impaired cardiac function, as measured in vivo and in vitro, that was restored by a blockade of C5a.…”

“…This suggests that, despite the rapid activation of the complement system after burn injury, limited beneficial effects of C5a blockade occur on the cellular level as early as 1 h, whereas it clearly takes longer (24 h) to fully engage the protective impact of anti-C5a. Our previous cellular studies have shown that the interaction of C5a-C5aR on CMs is a major contributor to the reduced LVP observed in vivo during sepsis (14). C5a and C3a have previously been shown to exert profound vasodilative effects on the systemic and coronary vasculatures that might exacerbate the myocardial contractile deficits in sepsis and partially explain the low systemic blood pressure values seen in septic humans and animal models (27,28).…”

“…A bilateral thoracotomy flap was created and the heart was rapidly excised and rinsed in ice-cold Krebs-Henseleit buffer supplemented with 5 mM taurine. The heart perfusion and the CM isolation procedures were performed as described previously (14). Briefly, the distal aortic arch was cannulated and mounted on a Langendorff perfusion system (ADInstruments) connected to a personal computer-based signal transduction/amplification system (PowerLab; ADInstruments).…”

“…Until recently, there has been little evidence for direct effects of C5a on parenchymal cells resulting in organ dysfunction. We have previously shown that C5a plays a central role in the induction of cardiomyocyte (CM) 4 contractility defects during sepsis (14). To date, the complement system has not been implicated in the pathogenesis of burn-induced myocardial dysfunction.…”

Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms

“…Overproduction of C5a and its receptor (C5aR), which is expressed on cells in the heart, lungs, liver and kidneys, could contribute to the dysregulated immune response characteristic of sepsis and multi-organ dysfunction. Niederbichler et al examined the effects of C5a in CLP-induced sepsis on rat hearts in vivo and isolated cardiomyocytes in vitro [32]. CLP resulted in significantly decreased left ventricular pressure in whole hearts, an effect reversed by administration of anti-C5a antibody (Ab) immediately after CLP.…”