Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. Dysfunction of endothelial cells is involved in CTEPH. The present study describes for the first time the molecular processes underlying endothelial dysfunction in the development of the CTEPH. The advanced analytical approach and the protein network analyses of patient derived CTEPH endothelial cells allowed the quantitation of 3258 proteins. The 673 differentially regulated proteins were associated with functional and disease protein network modules. The protein network analyses resulted in the characterization of dysregulated pathways associated with endothelial dysfunction, such as mitochondrial dysfunction, oxidative phosphorylation, sirtuin signaling, inflammatory response, oxidative stress and fatty acid metabolism related pathways. In addition, the quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach.
Highlights
Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death
To characterize the potential molecular mechanisms underlying endothelial dysfunction in the development of the CTEPH, patient-derived CTEPH-endothelial cells (ECs) and healthy Human Pulmonary Artery Endothelial Cells (HPAECs) were analyzed by label free quantitative proteomics approach. 3258 proteins and 27,678 unique peptides were identified and quantified. 673 proteins were differentially regulated of which 82 proteins were overexpressed, and 232 proteins resulted down-regulated in the CTEPH-ECs compared to the human pulmonary artery endothelial cells (HPAE) group, with a ratio’s threshold of 1.5
The mechanisms underlying endothelial dysfunction implicates the alterations in metabolism, inflammation and oxidative stress events. This is the first study to attempt the description of molecular network in in endothelial dysfunction associated with CTEPH using patient-derived pathological ECs
Summary
Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. The quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach. The vascular endothelium, constituted by a thin layer of endothelial cells (ECs), is at the interface between circulating blood and the vessel wall It regulates homeostasis, platelet activity, leukocyte adhesion and thrombosis[4,5]. Label free quantitative proteomics approach and network analysis of differentially regulated proteins in patient-derived cells provide a unique opportunity to investigate the molecular mechanisms of the disease
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