An altered left ventricle protein profile in human ischemic cardiomyopathy revealed in comparative quantitative proteomics

Abstract

IntroductIon With the ageing of the population, ischemic cardiomyopathy (ICM) is becoming an increasing social and economic burden to society. The best treatment strategy for ICM is heart transplant; however, the donors are currently scarce. 1 Thus, an enormous amount of clinical research has been undertaken to identify

Defining the Sarcomeric Proteoform Landscape in Ischemic Cardiomyopathy by Top-Down Proteomics

“…While ischemic heart disease is the leading cause of death worldwide, there are very few proteomics studies that have been performed directly using human ICM samples due to the difficulty in obtaining human heart tissue samples. , Roselló-Lletí et al analyzed cardiac protein changes in ICM from human LV tissues using two-dimensional gel electrophoresis followed by in-gel digestion and bottom-up MS, showing that proteins involved in cellular stress response, respiratory chain, and cardiac metabolism were altered . More recently, Yi et al quantitatively analyzed the LV proteome in human ICM using bottom-up LC–MS/MS and observed differentially expressed proteins related to metabolism, immune response, muscle contraction, and signal transduction . Nonetheless, bottom-up proteomics suffers from many limitations, including the protein interference problem and loss of vital information about PTMs and alternative splice variants due to the proteolytic cleave of intact proteins into peptides. , On the other hand, top-down proteomics can directly analyze intact proteins allowing for identification and characterization of proteoforms with full sequence coverage. − Therefore, top-down proteomics is ideally suited for studying human ICM at the proteoform level to reveal molecular changes within the human sarcomeric proteome.…”

“…67 More recently, Yi et al quantitatively analyzed the LV proteome in human ICM using bottom-up LC−MS/MS and observed differentially expressed proteins related to metabolism, immune response, muscle contraction, and signal transduction. 68 Nonetheless, bottom-up proteomics suffers from many limitations, including the protein interference problem and loss of vital information about PTMs and alternative splice variants due to the proteolytic cleave of intact proteins into peptides. 22,69 On the other hand, top-down proteomics can directly analyze intact proteins allowing for identification and characterization of proteoforms with full sequence coverage.…”

“…ICM is a highly heterogeneous cardiovascular disease that is characterized by significant alterations to the left ventricle of the heart, impacting systolic function and inducing myocardial hypoxia. While ischemic heart disease is the leading cause of death worldwide, there are very few proteomics studies that have been performed directly using human ICM samples due to the difficulty in obtaining human heart tissue samples. , Roselló-Lletí et al analyzed cardiac protein changes in ICM from human LV tissues using two-dimensional gel electrophoresis followed by in-gel digestion and bottom-up MS, showing that proteins involved in cellular stress response, respiratory chain, and cardiac metabolism were altered . More recently, Yi et al quantitatively analyzed the LV proteome in human ICM using bottom-up LC–MS/MS and observed differentially expressed proteins related to metabolism, immune response, muscle contraction, and signal transduction .…”

Construction of miRNAs and gene expression profiles associated with ischemic cardiomyopathy: Bioinformatics analysis

“…These genes and their signaling networks are involved in multiple physical and pathological processes including malaria and African trypanosomiasis [48], PI3K-Akt signaling, focal adhesion, protein digestion and absorption, complement and coagulation cascades [49], ECM-receptor interactions [26,49], and diabetic complications [50]. Advanced glycation end products and their receptors (AGEs/RAGE), which are implicated in diabetic complications such as diabetic cardiomyopathy [50], were linked to ICM, implying a role in the pathogenesis of ICM.…”

Multi‐omic analyses and network biology in cardiovascular disease

“…Putative PPIs were then predicted using bioinformatics‐based Ingenuity pathways analysis to identify cellular assembly and organization and cell cycle as the top enriched pathways differentially expressed in DCM [65]. Similar LC‐MS/MS analyses have also been used to profile the left ventricular proteomes of ICM patients, coupled with STRING analyses [66] of physical and functional protein interactions to identify metabolism, immune response, extracellular matrix, transcription/translation, cytoskeleton organization, cardiac muscle contraction, and intracellular signal transduction as upregulated subnetwork hubs [67]. An important limitation in quantitative proteomic profiling is the balance between increasing biological sample number versus greater depth of protein coverage within a sample.…”