Abstract 9534: Proteomic Signature of Right Ventricular Failure in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease leading to pulmonary artery pressure elevation and right ventricular (RV) failure. RV failure is the principal determinant of adverse outcomes in PAH patients and represents a major unmet medical need. Thus, a better understanding the pathogenesis of RV failure is mandatory. In this study, we used an unbiased proteomics approach to identify the molecular players engaged in RV failure development caused by PAH. Methods and Results: Proteomics analysis (nano-LC-MS/MS) was performed using control (autopsy, normal RV function, n=10), compensated (cRV, patients with RV hypertrophy and preserved cardiac index>2.2L/min/m 2 , n=10), and decompensated RV (dRV, PAH patients who died from RV failure, n=10). We identified 424 differentially expressed proteins between the dRV and control patients (p<0.05). Of these 424 proteins, 245 were upregulated and 179 were downregulated in the dRV. Using GO enrichment analysis and protein-protein interaction network, we found that upregulated proteins were significantly enriched in pathways involved in immune system and extracellular matrix organization, whereas downregulated proteins were mainly involved in muscle structure development, metabolism, and RNA splicing. To confirm the robustness and sensitivity of the expression changes observed in our proteomic data sets, expression levels of 3 selected proteins implicated in RNA splicing, namely heterogeneous ribonucleoprotein particle (HNRNP)-A1, -C1/C2 and -U, were measured by Western blotting. Consistent with the results of proteomics, these HNRNP proteins were markedly downregulated in dRV compared to cRV or controls (p<0.05). Similar results were observed in RV tissue samples from monocrotaline-injected and pulmonary artery banding-subject rats (n=7-10, p<0.05). In vitro , we demonstrated that knockdown of HNRNPA1 using siRNA prevents phenylephrine-induced cardiomyocyte (H9c2) hypertrophy, as assessed by immunostaining of F-actin and expression of Nppb . Further experiments are currently performed to decipher the role of HNRNPs in RV failure. Conclusions: Our data open novel perspectives for understanding molecular mechanisms of RV failure progression in PAH.
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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 | 0.000 |
| 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".