Role of complement C5a and histones in septic cardiomyopathy

Abstract

Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca]i-regulatory enzymes including sarco/endoplasmic reticulum Ca-ATPase (SERCA2) and Na/Ca exchanger (NCX) as well as Na/K-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…C5a reacts with its receptor, leading to cytokine storm, lymphocyte apoptosis, neutrophilic innate immune function loss, cardiomyopathy, disseminated intravascular coagulation, etc. Meanwhile, C5a also affects intracellular calcium homeostasis (Fattahi et al, 2018a;Ward and Fattahi, 2019). SCM is associated with decreased levels of three key enzymes (serca2, NCX, and Na+/K+-atpase) in cardiomyocytes, which are complement receptor-dependent (Fattahi et al, 2018a).…”

“…Meanwhile, C5a also affects intracellular calcium homeostasis (Fattahi et al, 2018a;Ward and Fattahi, 2019). SCM is associated with decreased levels of three key enzymes (serca2, NCX, and Na+/K+-atpase) in cardiomyocytes, which are complement receptor-dependent (Fattahi et al, 2018a). Some studies have suggested that histones may be a target for reducing cardiac dysfunction in sepsis.…”

New strategies for treatment of infectious sepsis

“…Reasons for septic cardiomyopathy could be traced to defects in Na + /K + ‐ATPase, which is critical for effective action potentials in CMs and in other cell types. Defects in sarco/endoplasmic reticulum Ca 2+ ATPase type 2 (SERCA2) and Na + /Ca 2+ (NCX) exchanger led to diastolic buildup of [Ca 2+ ]i in CMs in a manner that was associated with the inability to clear cytosolic [Ca 2+ ]i in CMs during diastole . Such events caused substantial dysfunction and apoptosis of CMs.…”

“…Finally, studies show a link between complement product of C5a and adverse outcomes in septic mice and in septic humans. Use of knockout (KO) mice (lacking C5a receptors; C5aRs) has been shown to protect against adverse events in the heart developing in sepsis . This emphasizes that certain manipulations can be done in septic mice that add important information on how sepsis causes organ dysfunction and might have application in septic humans.…”

The idea of fuzzy logic usage in a sheet-based FMEA analysis of mechanical systems

“…New proposals for the application of fuzzy logic met with great interest of scientific centres, which resulted in creation of many hybrid FMEA methods and models in the fuzzy environment, such as extended MULTIMOORA or AHP, applied e.g. by Fattahi [8] and Hu-Chen [9].…”