Abstract 4365971: Estrogen receptor alpha inhibits right ventricle cardiomyocyte NLRP3 inflammasome activation and restores right ventricular contractile function in low estrogen states
Bibliographic record
Abstract
Background: The NLRP3 inflammasome is implicated in right ventricular (RV) dysfunction, particularly in low endogenous estrogen states found in males and postmenopausal females. We hypothesized that NLRP3 inhibition through estrogen receptor alpha (ERα) enhances RV contractility and improves RV-pulmonary artery (PA) coupling. Methods: RVs from male and pre- or postmenopausal female PH patients with RV failure (RVF) were assessed for NLRP3 activation by analyzing proteomics data and staining for NLRP3 and ASC. Male or female human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were treated with endothelin-1 (ET1) ± 17beta-estradiol (E2). RV cardiomyocytes (RVCMs) were isolated from male and intact or ovariectomized female rats treated with monocrotaline (MCT) or pulmonary artery banding (PAB). Male or female ERα loss-of-function mutant (ERαmut) rats were employed to study the effects of ERα. RV-PA coupling was assessed by pressure-volume loops (PV-loops) in the WT and ERαmut MCT-treated rats. NLRP3 activation in RVCMs and iPSC-CMs was assessed by NLRP3-ASC colocalization and downstream targets. RVCM contractility and cytosolic calcium (c-Ca2+) were evaluated via IONOPTIX system. P<0.05 was considered significant. Results: Proteomics and immunofluorescence studies revealed that upregulation of NLRP3 activity and signaling in human RVF are more pronounced in males and postmenopausal females (p<0.05). In ET-1-treated iPSC-CMs, NLRP3 was more activated in male than female iPSC-CMs (p<0.05). RVCMs from male, but not female, MCT- or PAB-rats demonstrated increased NLRP3-ASC colocalization (p<0.05). E2 treatment prevented MCT-induced impairment of RV-PA coupling and had beneficial effects on survival. E2 treatment of male and OVX female wildtype (WT) rat RVCMs reduced NLRP3-ASC co-localization and increased Ca2+-dependent contractility (p<0.05). Similarly, E2 treatment in male iPSC-CMs prevented ET-1-induced NLRP3 activation. E2’s inhibitory effects on NLRP3 activation, impairment of RV-PA coupling, improved survival, NLRP3-induced contractile dysfunction, and c-Ca2+ in male WT rat RVCMs were abrogated in ERαmut rat RVCMs (p<0.05). Conclusion: NLRP3 activation impairs RV contractile function in a sexually dimorphic manner. The E2-ERα pathway protects against this dysfunction. E2 enhances RV function and survival in both male and postmenopausal models of RVF, suggesting its potential as a therapeutic target in low estrogen states.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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".