Conservation and divergence of protein pathways in the vertebrate heart

Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis). Determination of which proteins and protein pathways are conserved and which have diverged within these species will aid in our ability to choose the appropriate models for determining protein function and to model human disease. We uncover mammalian- and amphibian-specific, as well as species-specific, enriched proteins and protein pathways. Among these, we find and validate an enrichment in cell-cycle–associated proteins within Xenopus laevis. To further investigate functional units within cardiac proteomes, we develop a computational approach to profile the abundance of protein complexes across species. Finally, we demonstrate the utility of these data sets for predicting appropriate model systems for studying given cardiac conditions by testing the role of Kielin/chordin-like protein (Kcp), a protein found as enriched in frog hearts compared to mammals. We establish that germ-line mutations in Kcp in Xenopus lead to valve defects and, ultimately, cardiac failure and death. Thus, integrating these findings with data on proteins responsible for cardiac disease should lead to the development of refined, species-specific models for protein function and disease states.

心脏病是西方世界的首要致死病因。要从机制层面解析人类心脏发育与稳态平衡，以及相关疾病的分子基础，离不开动物模型的应用。本研究报道了4种拥有双循环系统的脊椎动物模型的心脏蛋白质组：家猪（Sus scrofa）、小家鼠（Mus musculus）以及两种蛙类——非洲爪蟾（Xenopus laevis）和热带爪蟾（Xenopus tropicalis）。明确这些物种中保守的蛋白质与蛋白质通路哪些具有保守性，哪些发生了分化，将有助于我们选择合适的模型来研究蛋白质功能，并构建人类疾病模型。我们发现了哺乳动物特异性、两栖动物特异性以及物种特异性富集的蛋白质与蛋白质通路。其中，我们在非洲爪蟾的心脏蛋白质组中验证并确认了细胞周期相关蛋白的富集现象。为进一步探究心脏蛋白质组内的功能单元，我们开发了一种计算方法，以分析不同物种间蛋白质复合物的丰度分布。最后，我们通过测试Kielin/chordin-like protein (Kcp)——一种在蛙类心脏中相较于哺乳动物更为富集的蛋白——的作用，验证了本数据集可用于预测适用于研究特定心脏病症的模型系统。我们证实，爪蟾体内Kcp的生殖系突变会引发瓣膜缺陷，最终导致心力衰竭与死亡。因此，将本研究发现与心脏疾病相关蛋白的研究数据相结合，将有助于开发更为精准的物种特异性蛋白质功能与疾病模型。