Biotechnology Research Institute, Montréal, Québec, Canada.
PLoS One. 2011;6(8):e22919. doi: 10.1371/journal.pone.0022919. Epub 2011 Aug 1.
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.
我们之前已经证明，当 C5 缺陷的 A/J 和重组同基因 BcA17 小鼠经静脉感染白念珠菌芽生孢子时，它们会出现心脏功能障碍。在这些研究中，我们观察到，即使在未感染的对照状态下，BcA17 心脏也表现出与母体 C5 充足的 C57Bl/6J（B6）小鼠相比与病理性心肌肥厚相关的基因表达改变。值得注意的是，Nppb 的表达增加，Nppb 是胎儿基因程序的一个成员，而 Rgs2 的表达减少，Rgs2 是肥厚反应的抑制剂。我们现在报告说，C5 缺失也影响了胎儿基因程序的其他元素的表达。此外，删除 C5a 受体 C5aR 的作用与删除 C5 基本相同，表明 C5a-C5aR 信号在表型中起着关键作用。由于在未感染状态下观察到病理表型，我们研究了 C5 在心脏应激反应中的作用。在之前的研究中，比较白念珠菌感染的 BcA17 和类似感染的 B6 心脏的表达谱表明，C5 缺陷心脏中缺乏心脏保护基因。为了确定这是否也与 C5 缺陷直接相关，我们在白念珠菌感染的 C5aR(-/-)小鼠中测试了 5 个这样的基因的表达。我们再次发现，C5aR 的缺失重现了 BcA17 应激反应的改变。为了确定我们的观察结果是否与其他形式的心脏损伤有关，我们测试了 C5 缺陷对白念珠菌感染引起的肥厚刺激的反应的影响。与我们的假设一致，A/J、BcA17 和 C5aR(-/-) 小鼠对白念珠菌感染的反应比 B6 和 BALB/c 小鼠表现出更高水平的 Nppa 表达。总之，我们的结果表明，功能性 C5a 的缺失使心脏处于困境状态，使心脏在面临额外损伤时易发生心脏功能障碍。
