Coronary dysfunction in Diet-induced Obese Mice Exposed to Long-term Intermittent Hypoxia: Therapeutic Potential of Mineralocorticoid Receptor Antagonists

Introduction: Obstructive sleep apnea (OSA) is characterized by repetitive obstruction in the upper airway leading to chronic intermittent hypoxia (IH). OSA is associated with increased cardiovascular morbidity with 70% of OSA individuals being obese. Previous studies suggest that mineralocorticoid receptor antagonists (MRAs) improve cardiac function. We investigated the impact of IH and obesity on coronary microvascular function and hypothesized that IH impairs coronary artery vascular reactivity, with MRAs, spironolactone (SPL), and finerenone (FIN), improving these effects. Methods: Male and female C57Bl/6J mice were fed a high-fat diet (HFD, 45% kcal of fat) or low-fat diet (LFD, 10% kcal of fat) for 10 weeks. Mice were then exposed to IH (12 cycles/hour at 6% FiO2 for 90 seconds per cycle) or room air (RA; 21% FiO2) for 12 hours per day over 16 weeks and treated with SPL, FIN or placebo mixed with the diet. Mean arterial blood pressure (MAP) was measured using the tail-cuff method. The left anterior descending coronary artery was harvested and examined for vascular reactivity in response to acetylcholine (ACh) and thromboxane A2 receptor agonist U46619. Results: MAP was increased in IH-HFD male mice, while MAP was unchanged in female mice. In males, IH and/or HFD augmented coronary vasoconstriction in response to U46619 and reduced ACh-mediated vasorelaxation. Meanwhile, in females, exacerbated vasoconstriction was observed only in the IH-HFD group and impaired vasorelaxation was shown in IH-placebo and IH-HFD groups. SPL and FIN normalized MAP in HFD, HFD-IH and LFD-IH male mice. In addition, FIN restored endothelium (Ach)-dependent relaxation in LFD-IH and HFD-IH male mice. FIN and SPL attenuated vasoconstriction only in LFD-IH group. However, in female mice, FIN or SPL did not ameliorate the enhanced vasoconstriction or the impaired vasorelaxation shown in the placebo corresponding groups. Conclusion: Findings suggest that males have a greater susceptibility to coronary dysfunction and hypertension associated with diet-induced obesity or long-term IH. Moreover, FIN, selective MRA, attenuated coronary dysfunction in IH-exposed mice, suggesting mineralocorticoid receptors as a promising therapeutic target to reduce cardiovascular consequences in OSA. NIH grants HL166617 and HL136386 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.