Abstract
Myocardial infarction (MI) triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, necessary for myocardial healing. Timely repression of inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains challenging. The ability of EVs to trigger a functional response upon delivery of carried bioactive cargos, have made them clinically attractive diagnostic biomarkers and vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with MI and from patients with stable angina (NMI). We report, for the first time, the proteomics profiling on 252 EV proteins that were modulated with >1.2-fold after MI. We identified six up-regulated biomarkers with potential for clinical applications; these reflected post-infarct pathways of complement activation (Complement C1q subcomponent subunit A (C1QA), 3.23-fold change, p = 0.012; Complement C5 (C5), 1.27-fold change, p = 0.087), lipoprotein metabolism (Apoliporotein D (APOD), 1.86-fold change, p = 0.033; Apolipoprotein C-III (APOCC3), 2.63-fold change, p = 0.029) and platelet activation (Platelet glycoprotein Ib alpha chain (GP1BA), 9.18-fold change, p < 0.0001; Platelet basic protein (PPBP), 4.72-fold change, p = 0.027). The data have been deposited to the ProteomeXchange with identifier PXD002950. This novel biomarker panel was validated in 43 patients using antibody-based assays (C1QA (p = 0.005); C5 (p = 0.0047), APOD (p = 0.0267); APOC3 (p = 0.0064); GP1BA (p = 0.0031); PPBP (p = 0.0465)). We further present that EV-derived fibrinogen components were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data demonstrated that plasma EVs contain novel diagnostic biomarkers and therapeutic targets that can be further developed for clinical use to benefit patients with coronary artery diseases (CADs).
Highlights
From the ‡School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551; §Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, and Cardiovascular Research Institute, Singapore 119228; ¶National University Heart Centre, Department of Cardiac, Thoracic & Vascular Surgery, Singapore 119228; ʈDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; **Experimental Cardiology Laboratory, Cardiology, University Medical Center Utrecht, the Netherlands & Interuniversity Cardiovascular Institute of the Netherlands, Utrecht, the Netherlands
Proteomics—Extracellular vesicles (EVs) released by host cells into the circulation have potential to inform clinicians about virtually any pathophysiological process that occurs in the human body [39, 40], and the relative ease with which these structures can be sampled from peripheral blood renders them highly attractive targets for prognostic testing
As the global population continues to age, the total burden of myocardial infarction (MI)-related morbidity and mortality is predicted to increase, there is an urgent need for efficacious clinical markers that can inform patient care and uncover novel therapies that can minimize myocardial tissue injury
Summary
We further present that EV-derived fibrinogen components were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data demonstrated that plasma EVs contain novel diagnostic biomarkers and therapeutic targets that can be further developed for clinical use to benefit patients with coronary artery diseases (CADs). The ability of EVs to exert potent influences on host cell and tissue function have been well established, it remains unclear whether the composition of circulating EVs is modified in MI, or whether these structures act as reservoirs of clinically useful biomarker that can inform patient care
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