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.
Highlights
The innate immune system uses a number of surface and intracellular sensing molecules to detect the presence of invading microbes or products derived from them, triggering a so-called ‘‘pro-inflammatory’’ response [1]
RNA showed that, in addition to a large set of genes whose expression was altered in response to C. albicans infection, a subset of genes was differentially expressed in a C5-dependent fashion, and this, prior to infection [17] (NCBI GEO accession number GSE3381)
It is notable that BcA17 shared the hypertrophic gene expression pattern with A/J, its C5-deficient parental strain and that C5aR deletion results in similar effects on cardiac gene expression, despite being on a distinct C5-sufficient background, that of BALB/c (B6 vs BALB/c p,0.001 for Nppb, Acta1, Myh7 and the Myh6/Myh7 ratio and p,0.05 for Nppa)
Summary
The innate immune system uses a number of surface and intracellular sensing molecules to detect the presence of invading microbes or products derived from them, triggering a so-called ‘‘pro-inflammatory’’ response [1]. C5a is essential for the recruitment and activation of inflammatory cells such as granulocytes [2] and it mediates its effect primarily by binding a G-protein coupled receptor (GPCR), C5aR (or CD88) [2,3]. Another C5a-binding receptor C5L2 (or GPR77) [4], has been described relatively recently. Inhibition of C5a activity is an attractive strategy to treat or prevent a number of clinical conditions caused by excessive complement activation
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