Ninjurin-1 Deletion Prevents Pulmonary Hypertension in the Monocrotaline Rat Model of Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Abstract RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal form of pulmonary hypertension (PH) characterized by progressive remodeling of the pulmonary vasculature and right ventricle (RV)1. The inflammatory response driven in part by lytic cell death contributes to PAH pathogenesis3. These lytic cell death pathways, such as pyroptosis and post-apoptosis lysis, require the protein ninjurin-1 (NINJ1) to execute cellular rupture4-6. Given that several molecules known to contribute to PAH require cellular lysis for their release, it follows that NINJ1 may be a key driver of the disease process. Yet, the role of NINJ1 in PAH development has not been investigated. We hypothesize that NINJ1-mediated cell rupture contributes to PAH development, and that the inhibition of NINJ1 will prevent disease progression, thereby identifying NINJ1 as a novel therapeutic target. METHODS: PH was induced in wild-type (WT) and Ninj1 knockout (KO) rats on a Sprague Dawley background using the monocrotaline (MCT) model. Rats were treated with MCT (40 mg/kg; intraperitoneal), then followed for three weeks prior to endpoint analysis. Disease severity was assessed by right ventricular systolic pressure (RVSP) measured by closed-chest right heart catheterization. RV hypertrophy was assessed using the Fulton index. Pulmonary vascular remodeling was assessed by medial vessel wall thickness. Cellular rupture was assessed in WT and Ninj1 KO rat bone marrow-derived macrophages (BMDMs) using a lactate dehydrogenase (LDH) assay following induction of pyroptosis (nigericin) or apoptosis (venetoclax or doxorubicin). RESULTS:Ninj1 KO BMDMs released significantly less LDH compared to WT cells following cell death induction, confirming the role of NINJ1 in cellular rupture. As compared to WT animals following MCT administration, Ninj1 KO rats displayed decreased RVSP (KO: 37.14 mmHg, n=15; WT: 79.07 mmHg, n=11; P<0.0001) and Fulton index (KO: 0.21, n=15; WT: 0.31, n=12, P<0.0001), indicating decreased PH and RV hypertrophy, respectively. Ninj1 KO rats also displayed decreased pulmonary vascular remodeling compared to WT animals (P<0.0001). No significant basal differences between genotypes were observed in untreated rats. CONCLUSION: Our data demonstrates that Ninj1 KO prevents PAH development in the MCT model. By identifying NINJ1 as a therapeutic target in PAH, our work will add to our arsenal of translational therapies for this devastating disease. Thus, our future directions include validating our findings in other preclinical models and conducting an intervention trial of NINJ1 inhibition in established PH.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".