Evaluating the effectiveness of an apelin analog as a potential treatment for pulmonary arterial hypertension using a sugen-hypoxia rat model
Bibliographic record
Abstract
Background: Pulmonary arterial hypertension (PAH) is a debilitating syndrome characterized by heightened pulmonary arterial pressures, and adverse pulmonary vascular remodeling. Eventually, the right ventricle (RV) decompensates, and fatal right heart failure ensues. Existing treatments for PAH are ineffective at improving survival. Apelin is an endogenous cardioprotective peptide, and disruption of apelin signaling was associated with the development of PAH. Restoring the activity of the apelin pathway is a promising approach in reversing the arteriopathy underlying PAH to protect the RV. The salutary actions of apelin are limited by its short half-life; recently, apelin analogs designed with extended half-lives offer a novel therapeutic avenue requiring further testing. Objective: Our project aims to evaluate the effectiveness of an apelin analog as a potential treatment for PAH using a Sugen-Hypoxia (SuHx) rat model of PAH which recapitulates disease characteristics seen in humans. We hypothesize that the apelin analog treatment will improve pulmonary hemodynamics and preserve RV adaptation in rats exposed to SuHx and assuage the pulmonary arteriopathy seen in PAH rats. Experimental design: Male Sprague Dawley rats aged 9 weeks were randomly split into a placebo or treated PAH group. For 3 weeks, a control group was kept within normal room air while the placebo and treated PAH rats were kept in a hypoxia chamber (10% O 2 ). Placebo and treated rats were injected with SU5416 (20 mg/kg, SQ) once at the start of the 3 weeks to induce disease. The normoxic period lasted 5 weeks following the 3 weeks of hypoxia. Treated rats received apelin analog (0.5 μmol/kg, IV, b.i.d.) for the final 3 weeks of normoxia; the placebo group received the same dose of saline. Results: At endpoint, glomerular filtration rate (GFR) measurements showed that placebo treated (PAH-P) PAH rats had reduced GFR while apelin treated (PAH-A) PAH rats had recovered GFR. Echocardiography revealed that PAH-A rats had improved cardiac function compared to PAH-P rats. RV Pressure-volume loop surgeries showed that PAH-A rats had ameliorated RV hemodynamic pressures in contrast to PAH-P rats. Histological analysis demonstrated reduced cardiac fibrosis and hypertrophy, and fewer formations of pulmonary vascular lesions within PAH-A rats compared to PAH-P rats. Single nucleus RNA sequencing performed on RV and lung tissue delineated mitigation of disease progression within the PAH-A group compared to PAH-P rats. Electrocardiography recordings showed more severe electrical remodeling in the PAH-P group compared to the PAH-A rats. Conclusions & significance: Rats with PAH treated with apelin had overall improved cardiopulmonary health outcomes compared to placebo treated PAH rats. The results of this study provide insight into the beneficial role of the apelin pathway in the setting of PAH to propose a new treatment for patients with PAH to improve their duration and quality of life. Canadian Institutes of Health Research Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".