Protein network analyses of pulmonary endothelial cells in chronic thromboembolic pulmonary hypertension

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

The authors acknowledge support from the University of Milan through the APC initiative. The authors acknowledge support from Unitech OMICs, University of Milan through MS raw data' acquisition. This present work was funded by Horizon 2020 program of the European Union-Marie Sklodowska-Curie Actions, Innovative Training Networks (ITN), Call: H2020-MSCA-ITN-2015, Number: 675527-MOGLYNET. Tura-Ceide was the recipient of Marie Curie Post-Doctoral Fellowship Award BIOTRACK: IDIBAPS, Spanish Society of Respiratory Medicine (SEPAR 2013), Catalan Society of Pneumology (SOCAP 2015), Fundacion Contra la Hipertension Pulmonar (FCHP). Barbera was funded by Generalitat de Catalunya (2017-SGR-00617). Cascante was funded by Generalitat de Catalunya (2017SGR1033 from AGAUR and "Icrea Academia Award" from Icrea Foundation) and MINECO-European Commission FEDER funds-"Una manera de hacer Europa" (SAF2017-89673-R). Tura-Ceide, Barbera and Cascante were funded by the Institute of Health Carlos III, Spain (OTC: CP17/00114, PI18/00960; JAB: PI15/00582; MC: CIBEREHD-CB17/04/00023 and PT17/0009/0018). Cofunding was provided by the Fondo Europeo de Desarrollo Regional (FEDER); "Una manera de hacer Europa"