Unknown,Transcriptomics,Genomics,Proteomics

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Characterisation of Myocardial Infarction and Unstable Angina with mRNA Profiles from Whole Blood of individual patients

ABSTRACT: Coronary artery disease (CAD) remains a leading cause of death worldwide. Acute coronary syndromes (ACS) are the spectrum of diseases arising from coronary atherosclerotic plaque rupture, ranging from unstable angina (UA; clinical symptoms of cardiac ischemia without myocardial necrosis) to myocardial infarction (MI; clinical symptoms of cardiac ischemia with myocardial necrosis). We use microrray to identify changes in pathways following MI.This study examines mRNA expression levels in human whole blood at 7 and 30 days post ACS. Patients with MI are compared to those with UA (not healthy controls), thus focusing on differences in mRNA expression due to the acute clinical events rather than underlying atherosclerosis and its treatment. We recruited 26 patients presenting with acute coronary syndromes (ACS); 8 with unstable angina (UA) and 18 with MI. Supplementary files: The files contain the combined values (for each group) of the single patients' expression levels, the fold changes and the significance levels associated. Gene expression levels were estimated using probabilistic models implemented in puma (Propagating Uncertainty in Microarray Analysis, bioconductor.org), which provide estimates for the variance and credibility interval for probe level errors of each transcript. FCs were calculated after combining gene expression values within groups using Bayesian hierarchical model, incorporating probe level errors into the variance estimate. Significance levels for differentially expressed genes were detected by calculating the probability of positive log ratio (PPLR). The higher is the probability the more confident is the estimate of that positive FC, conversely the lower is the probability the more confident is the estimate of that FC to be negative. This model was implemented in the pumaComb and pumaDE modules within puma. file1 = mRNA_MI_combday30_exprs file2 = mRNA_MI_combDay7_exprs

ORGANISM(S): Homo sapiens

SUBMITTER: Marta Milo

PROVIDER: E-GEOD-29111 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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.

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Characterisation of Myocardial Infarction and Unstable Angina with mRNA Profiles from Whole Blood of individual patients

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