Conservation and divergence of protein pathways in the vertebrate heart

Abstract

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.

Proteomics Dissection of Cardiac Protein Profiles of Humans and Model Organisms

“…3b). These findings are in line with previous reports 16 and underscore essential characteristics of the heart, such as its high energy demand. Among clusters that were significantly different between species, we found highest enrichment of cytoplasmic, vesicular and mitochondrial proteins, proteins involved in binding and localization, RNA, peptide and small molecule metabolic and catabolic pathways, as well as proteins with structural molecule activity ( Fig.…”

“…Specifically, we present a quantitative high-resolution map of cardiac protein expression across humans and five common model organisms. Previous studies of model organisms have illuminated portions of their cardiac proteomes 10,19,20 , but often with a particular focus such as cardiac development 21 , disease models 22 , subcellular protein expression 23,24 , phosphorylation [25][26][27] , protein turnover 8,28 or focused on smaller mammals and amphibians 16 or human tissue collected several days post-mortem 29 . No study has been presented that allowed for direct comparison of cardiac protein profiles between model organisms and human.…”

Antibodies, Nanobodies, or Aptamers—Which Is Best for Deciphering the Proteomes of Non-Model Species?

“…A recent study sought to elucidate the proteomes of cardiac development in the mouse, pig, and Xenopus to better understand the most appropriate model for modelling cardiac disease. Proteins known to be expressed in humans were also found to be enriched in frogs, but surprisingly not in mice or pigs [35]. It is unsurprising then that frogs may find their way into more translatable research in the future [36], especially given that half of human genes differ from their mouse orthologs in different developmental trajectories, including more than 200 disease genes associated with brain, heart, and liver diseases [37].…”

Quantitative proteome comparison of human hearts with those of model organisms

“…Focused proteomics efforts on cardiac tissue from humans have underscored major protein differences across cardiac chambers [14]. Studies analyzing hearts from various species have outlined particular differences in sarcomeric proteins [15] as well as species-specific pathways [16]. Here, we utilized mass AU : Anabbreviationlisthasbeencompiledforthoseusedthroughoutthetext:Pleaseverifyiftheentriesarecorr spectrometry-based methods to assess species-and region-specific protein composition of cardiac tissues.…”