A novel role for the fifth component of complement (C5) in cardiac physiology
Alaka Mullick1, Jessy Tremblay, Zully Leon
1Biotechnology Research Institute, Montréal, Québec, Canada. alaka.mullick@cnrc-nrc.gc.ca
Insights
Complement component 5 (C5) deficiency predisposes hearts to dysfunction and pathological hypertrophy. Absence of C5 or its receptor (C5aR) impairs cardiac stress response, increasing susceptibility to injury.
Area of Science:
- Immunology
- Cardiovascular Biology
- Genetics
Background:
- C5-deficient mice (A/J, BcA17) exhibit cardiac dysfunction upon Candida albicans infection.
- Uninfected BcA17 hearts show gene expression changes linked to pathological cardiac hypertrophy compared to C5-sufficient B6 mice.
- Key genes like Nppb (increased) and Rgs2 (decreased) indicate altered cardiac states.
Purpose of the Study:
- To investigate the role of C5 and its signaling pathway in cardiac health and response to injury.
- To determine if C5a-C5aR signaling is critical for cardiac phenotype and stress response.
- To assess the impact of C5-deficiency on cardiac response to different types of stress, including infection and drug-induced hypertrophy.
Main Methods:
- Comparative gene expression analysis in C5-deficient (BcA17) and C5-sufficient (B6) mice.
- Investigation of C5a receptor (C5aR) knockout mice to elucidate C5a signaling.
- Assessment of cardiac gene expression in response to Candida albicans infection and isoproterenol-induced cardiac stress.
Main Results:
- C5-deletion affects fetal gene program elements; C5aR deletion mirrors C5 deletion's effects.
- C5-deficient hearts show a reduced expression of cardioprotective genes during C. albicans infection.
- C5-deficient mice exhibit elevated Nppa expression following isoproterenol stimulation, indicating heightened cardiac stress response.
Conclusions:
- Absence of functional C5a signaling creates a state of cardiac distress.
- C5-deficiency confers a predisposition to cardiac dysfunction when the heart faces additional injury.
- C5a-C5aR pathway is a critical regulator of cardiac homeostasis and stress resilience.
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.
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