Intermittent hypoxia combined with diet and Finerenone treatment significantly altered cellular heterogeneity in the mouse aorta (p = 0.004), inducing cell-type-specific transcriptional reprogramming.
Single-cell RNA sequencing reveals that intermittent hypoxia, diet, and finerenone treatment induce distinct, cell-type-specific transcriptional reprogramming in the mouse aorta.
p-value: p=0.004
Abstract Rationale Obstructive sleep apnea (OSA) is characterized by recurrent episodes of intermittent hypoxia (IH) with links to cardiovascular disease. Despite substantial research on the cardiovascular consequences of IH associated with OSA, the fundamental cellular-specific responses to dietary and pharmacological interventions, such as mineralocorticoid receptor antagonists (MRA), require further research. To address this gap, we applied single-cell RNA sequencing (scRNA-seq) to outline transcriptional changes across distinct cell populations in the aorta of mice exposed to IH compared to normoxic controls. Methods Male C57Bl/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 10 weeks, followed by IH exposures (FiO2 cycles of 21% for 90s and 6% for 90s) or room air (RA, 21%) for 12 hours/day over 16 weeks. Mice were treated with the MRA Finerenone (FIN) or placebo for 16 weeks along with IH-exposure (n = 4 mice/group). Aorta tissue was harvested and dissociated into single-cell suspensions for scRNA-seq library preparation using the Scale Biosciences Single Cell RNA Sequencing Kit v1.1. After quality control and filtering, cells were analyzed using the Seurat library in R for clustering and differential expression. Results This analysis revealed distinct transcriptional signatures induced by IH across multiple cell types, specifically varying in response to diet and treatment. Cellular heterogeneity in the aorta significantly differed (p = 0.004, One-Way ANOVA) across the experimental groups, suggesting an altered cellular response to IH with dietary and pharmacological interventions. Differential gene expression reveals specific pathways suggesting that IH induces transcriptional reprogramming in a cell-type-dependent manner with diet and treatment influencing the cellular response. Conclusion Our findings indicate that IH, when combined with diet-induced obesity and treatment, stimulates cell-type-specific responses that may contribute to the systemic effects of sleep apnea. These findings provide a foundation for future studies into therapeutic strategies aimed at mitigating IH-induced pathology in OSA patients, particularly in the context of cardiometabolic comorbidities. This abstract is funded by: NIH grant HL166617
Cataldo et al. (Fri,) conducted a other in Obstructive sleep apnea / Intermittent hypoxia. Intermittent hypoxia, high-fat diet, and Finerenone vs. Room air, low-fat diet, and placebo was evaluated on Cellular heterogeneity in the aorta (p=0.004). Intermittent hypoxia combined with diet and Finerenone treatment significantly altered cellular heterogeneity in the mouse aorta (p = 0.004), inducing cell-type-specific transcriptional reprogramming.
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