A Novel Role for the Fifth Component of Complement (C5) in Cardiac Physiology

Abstract

We have previously demonstrated that C5-deficient A/J and recombinant congenic BcA17 mice suffer from cardiac dysfunction when infected with C. albicans blastospores intravenously. During these studies we had observed that, even in the control un-infected state, BcA17 hearts displayed alterations in gene expression that have been associated with pathological cardiac hypertrophy in comparison to parental C5-sufficient C57Bl/6J (B6) mice. Of note was an increase in the expression of Nppb, a member of the fetal gene program and a decrease in the expression of Rgs2, an inhibitor of the hypertrophic response. We now report that C5-deletion has also affected the expression of other elements of the fetal gene program. Moreover deleting the C5a receptor, C5aR, has essentially the same effect as deleting C5, indicating a key role for C5a-C5aR signaling in the phenotype. Having noted a pathological phenotype in the un-infected state, we investigated the role of C5 in the response to cardiac stress. In previous studies, comparison of the expression profiles of C. albicans-infected BcA17 and similarly infected B6 hearts had revealed a paucity of cardioprotective genes in the C5-deficient heart. To determine whether this was also directly linked to C5-deficiency, we tested the expression of 5 such genes in the C. albicans-infected C5aR−/− mice. We found again that deletion of C5aR recapitulated the alterations in stress response of BcA17. To determine whether our observations were relevant to other forms of cardiac injury, we tested the effect of C5-deficiency on the response to isoproterenol-induced hypertrophic stimulation. Consistent with our hypothesis, A/J, BcA17 and C5aR−/− mice responded with higher levels of Nppa expression than B6 and BALB/c mice. In conclusion, our results suggest that an absence of functional C5a renders the heart in a state of distress, conferring a predisposition to cardiac dysfunction in the face of additional injury.

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

“…C5a 1 receptor has been shown to control osteoblast migration during fracture healing (Ignatius et al, 2011a), and efficient osteoclast differentiation requires local complement activation (Ignatius et al, 2011b). Normal heart function appears to depend on the C5a/C5a 1 receptor axis, with C5 deficiency and receptor knockout or blockade causing a "state of distress" (Mullick et al, 2011). C3a also has positive effects on food intake regulation, with the administration of C3a to the central nervous system leading to suppression of appetite (Ohinata et al, 2002(Ohinata et al, , 2007(Ohinata et al, , 2009Ohinata and Yoshikawa, 2008).…”

A vital role for complement in heart disease

“…Zhang et al recently demonstrated complement activation during hypertension and that a C5a receptor signaling pathway on blood monocytes/macrophages played a pathological role in angiotensin II-induced cardiac inflammation and remodeling (Zhang et al, 2014). Conversely, C5a-receptor deficiency in a murine knock-out model has been associated with decreased resistance to cardiac stress, underscoring that complement might act as a double-edged sword also in the heart (Mullick et al, 2011). The mechanisms for in situ increased complement activation in heart failure are currently unknown, but myocardial levels of complement factor B are upregulated after myocardial infarction through toll-like receptor signaling and inflammatory cytokines (Singh et al, 2009;Singh et al, 2012).…”

The Alternative C5a Receptor Function

“…It is generally thought that the C5aR-mediated classical PI3K signal is controlled by the ERK1/2 pathway. Moreover, neutrophil in fl ux is decreased following the injection of bacterial endotoxin into the peritoneal cavity in C5-de fi cient mice (Mullick et al 2011 ;Snyderman et al 1971 ) . It is believed that the neutrophil C5aR works as a pro-in fl ammatory receptor during the initiation phase of acute in fl ammation.…”