Phosphoproteomic Analysis of Platelets in Severe Obesity Uncovers Platelet Reactivity and Signaling Pathways Alterations

Maria N. Barrachina, Lidia Hermida-Nogueira, Luis A. Moran, Vanessa Casas, Sarah M. Hicks, Aurelio M. Sueiro, Ying Di, Robert K. Andrews, Steve P. Watson, Elizabeth E. Gardiner, Joaquin Abian, Montserrat Carrascal, Maria Pardo, Angel Garcia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

OBJECTIVE: Obesity is associated with a proinflammatory and prothrombotic state that supports atherosclerosis progression. The goal of this study was to gain insights into the phosphorylation events related to platelet reactivity in obesity and identify platelet biomarkers and altered activation pathways in this clinical condition. APPROACH AND RESULTS: We performed a comparative phosphoproteomic analysis of resting platelets from obese patients and their age- A nd gender-matched lean controls. The phosphoproteomic data were validated by mechanistic, functional, and biochemical assays. We identified 220 differentially regulated phosphopeptides, from at least 175 proteins; interestingly, all were up-regulated in obesity. Most of the altered phosphoproteins are involved in SFKs (Src-family kinases)-related signaling pathways, cytoskeleton reorganization, and vesicle transport, some of them validated by targeted mass spectrometry. To confirm platelet dysfunction, flow cytometry assays were performed in whole blood indicating higher surface levels of GP (glycoprotein) VI and CLEC (C-type lectin-like receptor) 2 in platelets from obese patients correlating positively with body mass index. Receiver operator characteristics curves analysis suggested a much higher sensitivity for GPVI to discriminate between obese and lean individuals. Indeed, we also found that obese platelets displayed more adhesion to collagen-coated plates. In line with the above data, soluble GPVI levels-indicative of higher GPVI signaling activation-were almost double in plasma from obese patients.

Original languageEnglish
Pages (from-to)478-490
Number of pages13
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 2021
Externally publishedYes

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