Endothelial Colony-Forming Cell Transcriptomic Profiling in CT-defined Coronary Artery Disease from the BioHEART-CT Study Implicate CCBE1 in Mitochondrial Dysfunction-associated Atherosclerosis
Bibliographic record
Abstract
Abstract Background Endothelial dysfunction is an early contributor to atherosclerosis. This study combined CT imaging of coronary artery disease (CAD) and patient-dervied endothelial colony-forming cells (ECFCs) transcriptional profiling to investigate potential mechanisms underlying endothelial dysfunction in atherosclerosis. Methods Twenty-six individuals with CT-defined CAD and eighteen non-CAD controls were included in the Discovery Cohort for bulk RNA sequencing and transcriptomic analysis of ECFCs. Differential gene expression analysis was performed, and candidate genes were selected based on logFC and p-value. Candidate genes were carried forward for gene expression validation using quantitative real-time PCR (qRT-PCR) in a Validation Cohort. Mitochondrial reactive oxygen species (mROS) production and mitochondrial mass were assessed using multi-colour flow cytometry. Functional validation of the top candidate was conducted in using human umbilical vein endothelial cells (HUVECs) using loss-of-function genetic approach. Expression Quantitative Trait Loci (eQTL)-association analysis was conducted using genotype data from the BioHEART-CT cohort. Results Pairwise analysis identified six differentially expressed protein-coding genes in CAD ECFCs: CCBE1 (Collagen and Calcium Binding EGF Domain-Containing 1), SPINT2, CRISPLD1, PIEZO2, EPB41L3 , and AC005943.1 . qRT-PCR in the Validation Cohort confirmed significantly higher CCBE1 expression in CAD patients. Individuals with relative CCBE1 fold change expression>10 had a 2.8-fold increase in the log-odds ratio of CT-defined CAD. CAD ECFCs displayed elevated mROS and mitochondrial mass. CCBE1 knockdown in HUVECs reduced mROS and mitochondrial mass without affecting proliferation or permeability, but shifted cells into a metabolically elevated state, marked by increased ATP production, respiration and glycolysis. CCBE1 cis-eQTLs were associated with increased odds of CAD in the BioHEART-CT cohort. Conclusions CCBE1 expression in ECFCs was higher in patients with CT-defined CAD versus non-CAD. Quantitative assessment of transcript levels supported a causal relationship between greater CCBE1 expression and CAD burden and risk, and functional experiments on CCBE1 knockdown demonstrated improved mitochondrial function in human endothelial cells. GRAPHICAL ABSTRACT Novelty and Significance What is Known? The endothelium plays a critical role in vascular health and susceptibility to atherosclerosis. Mitochondrial dysfunction has been implicated in atherosclerosis, but its role and mechanism in individual susceptibility to CAD in humans is not known. What New Information Does This Article Contribute? Novel approach integrating CT imaging with ECFC functional data to link vascular structure with endothelial biology ex vivo . Patients with CT-defined CAD had 3.6-fold higher CCBE1 expression compared to non-CAD within the Validation Cohort. Cis -eQTL-association analysis revealed increased odds of CAD. CCBE1 knockdown improved mitochondrial function in human endothelial cells. Together, these 4 lines of evidence point to a novel and causal role for CCBE1 in human CAD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".