Dataset Information

Plasma-derived extracellular vesicles contain predictive biomarkers and potential therapeutic targets for myocardial ischemic injury

ABSTRACT: Myocardial infarction (MI), an undesirable clinical outcome of coronary artery disease (CAD), triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, which is necessary for myocardial healing. However, when in excess, causes pathological tissue remodeling and eventual heart failure. Timely repression of MI-induced inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains clinically challenging. The well documentation on the ability of EVs to trigger a functional response with the delivery of bioactive cargos carried within, have made them clinically attractive as diagnostic biomarkers and drug vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with (MI) and from control patients with stable angina (NMI). We report, for the first time, the expression proteomics profiling on 252 plasma EV proteins that were modulated with >1.2-fold in myocardial injury. We identified a panel of six strongly up-regulated biomarkers with significant 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 successfully validated in a separate cohort of 43 individual angina patients using Luminex analysis of the representative EV proteins C1QA (p = 0.005) and C5 (p = 0.0021), which act as critical regulators of complement activity in MI. We further present that all EV-derived fibrinogen components detected were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, and indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data urge the further development of novel EV-based diagnostic and therapeutic strategies to benefit patients with CAD.

INSTRUMENT(S): LTQ FT

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Esther Cheow

LAB HEAD: Newman Siu Kwan SZE

PROVIDER: PXD002950 | Pride | 2016-05-31

REPOSITORIES: Pride

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Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury.

Cheow Esther Sok Hwee ES Cheng Woo Chin WC Lee Chuen Neng CN de Kleijn Dominique D Sorokin Vitaly V Sze Siu Kwan SK

Molecular & cellular proteomics : MCP 20160527 8

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 attra ...[more]

PMID: 27234505

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Project description:Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation. A microarray study was performed on whole blood from two healthy donors, a C5-deficient patient (C5D) (with and without C5-reconstitution) incubated for 120 min at 37oC with (i) PBS, (ii) E. coli or (iii) E. coli and inhibitors of complement (C3 or C5aR) and/or CD14 or inhibitor controls. The experiments were performed as biological replicates on two different days (healthy donor and C5D). Due to lack of a second C5-deficient patient, microarray analyses were prerformed twice (technical replicate) for C5D and day 1. Expression data in presence of PBS were used as reference for those in pressence of E. coli. Expression data in presence of E. coli were used as reference for those in pressence of E. coli and inhibitors. Expression data from 0 min incubation with PBS represent the initial state (T0). Whole blood was lysed in Applied Biosystems AB6100 total RNA chemistry lysis buffer and stored at -80oC prior to RNA extraction.

			Action	DRS
	MI_PlasmaEV_A.msf	Msf
	MI_PlasmaEV_A.pep.xml	Pepxml
	MI_PlasmaEV_A.prot.xml	Xml
	MI_PlasmaEV_AB.msf	Msf
	MI_PlasmaEV_AB.pep.xml	Pepxml