Sizing up models of heart failure: Proteomics from flies to humans

Abstract

Cardiovascular disease is the leading cause of death in the western world. Heart failure is a heterogeneous and complex syndrome, arising from various etiologies, which result in cellular phenotypes that vary from patient to patient. The ability to utilize genetic manipulation and biochemical experimentation in animal models has made them indispensable in the study of this chronic condition. Similarly, proteomics has been helpful for elucidating complicated cellular and molecular phenotypes and has the potential to identify circulating biomarkers and drug targets for therapeutic intervention. In this review, the use of human samples and animal model systems (pig, dog, rat, mouse, zebrafish, and fruit fly) in cardiac research is discussed. Additionally, the protein sequence homology between these species and the extent of conservation at the level of the phospho-proteome in major kinase signaling cascades involved in heart failure are investigated.

Keywords: Animal models; Heart failure; Posttranslational modifications.

Figure 1

(A) Venn diagrams showing the number of proteins with ≥90% amino acid sequence homology between human, dog and pig (left); human, mouse and rat (middle); and human, zebrafish, and fruit fly (right) proteomes. CD-HIT generated protein clusters at ≥90% homology were used to identify representative proteins common across species and unique to each species, and used to create the Venn diagrams. (B) Summary of the advantages and disadvantages of the various animal models for HF research. (C) Number of peer-reviewed articles about HF on the publically available database Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/), including reviews and primary articles using human, pig, dog, rat, mouse, zebrafish, or fruit fly models. The bar graph for human includes basic and clinical HF research. Pubmed was queried for all scientific papers published with key word “heart failure” from 1916 to August 2013. A total of 131 643 articles were returned.

Figure 2

(A) Number of publications on Pubmed involving the PTMs phosphorylation, O-GlcNac, and acetylation associated with HF. In total, there were 1423, 55, and 4 articles published on phosphorylation, acetylation, and O-GlcNac modifications respectively. (B) Articles published involving phosphorylation and HF in humans (black bars) or mice (white bars) were sorted by kinase (PKA, PKC, PKG, AKT, GSK-3β, and TGF-β). Note that if there were articles containing more than one of the kinases searched for, the same article was counted more than once.

Figure 3

(A) High confidence score based network of the GSK-3β/AKT and PKA pathways created using STRING . Conservation (amino acid sequence homology) level of GSK-3β and AKT in the GSK-3β/AKT pathway across the seven species shows very high homology from human to fruit fly, suggesting their importance in cardiac function. (B) The conservation levels of the individual proteins of the PKA pathway show that all PKA subunits (PRKAR and PRACA) have a high degree of amino acid sequence homology from human to fruit fly.