Abstract 4145905: NLRP3 signaling in rodent and human right ventricular failure is sexually dimorphic and regulated by 17β-estradiol via estrogen receptor α
Bibliographic record
Abstract
Introduction: Estrogen receptor α (ERα) promotes cardioprotective signaling in right ventricle cardiomyocytes (RVCMs). NLRP3 inflammasome activation in macrophages contributes to RV failure (RVF) development in pulmonary hypertension (PH). However, NLRP3 signaling in RVCMs has not been studied. We hypothesized that NLRP3 inflammasome activation mediates RVCM contractile dysfunction and is attenuated by 17β-estradiol (E2) via ERα. Methods: RVs from male or female PH patients with RVF were assessed for NLRP3 activation by analyzing RNA-seq and proteomics data, plus staining for NLRP3 and its binding partner ASC. Male or female human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were treated with endothelin-1 (ET1) ± E2. RVCMs were isolated from male or female monocrotaline (MCT) or pulmonary artery banding (PAB) rats. RVCMs were also isolated from healthy rats and treated with ET1 ± E2 in vitro. Male or female ERα loss-of-function mutant (ERα mut )] rats were employed to study effects of ERα. NLRP3 activation in RVCMs and iPSC-CMs was assessed by NLRP3-ASC colocalization and activation of downstream targets. RVCM contractility and cytosolic calcium (c-Ca 2+ ) were evaluated via IONOPTIX system. P<0.05 was considered significant. Results: RNA-seq, proteomics, and immunofluorescence studies revealed that upregulation of NLRP3 activity and signaling in human RVF are more pronounced in males (p<0.05 for all comparisons). In male patients, NLRP3 activation was inversely correlated with cardiac index (p<0.05). In pilot studies, NLRP3 was more activated in male vs female ET1-treated iPSC-CMs. RVCMs from male, but not female, MCT- or PAB-rats demonstrated increased NLRP3-ASC colocalization (p<0.05). RVCMs treated with ET1 exhibited more NLRP3 activation and contractile dysfunction than female RVCMs (p<0.05). E2 treatment in male WT RVCMs reduced NLRP3-ASC co-localization and increased Ca 2+ dependent contractility (p<0.05). E2 treatment in male iPSC-CMs trended to prevent ET1-induced NLRP3 activation. E2’s inhibitory effects on NLRP3 activation, NLRP3-induced contractile dysfunction, and c-Ca 2+ in male WT RVCMs were abrogated in ERα mut RVCMs (p<0.05). Conclusion: NLRP3 activation in human and rat RVF as well as NLRP3-induced contractile dysfunction in human iPSC-CMs and rat RVCMs exhibit a male bias. E2, via ERα, prevents NLRP3 activation and NLRP3-induced contractile dysfunction. Inhibiting NLRP3 via E2-ERα may be a novel treatment strategy for RVF.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.009 | 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".