矿糖皮质激素受体拮抗剂可预防间歇性缺氧时冠状动脉微血管功能障碍。

IF 4.9 2区 医学 Q1 Medicine
Sleep Pub Date : 2025-09-09 DOI:10.1093/sleep/zsae296
Mohammad Badran, Abdelnaby Khalyfa, Chastidy A Bailey, David Gozal, Shawn B Bender
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引用次数: 0

摘要

研究目的:阻塞性睡眠呼吸暂停(OSA),以间歇性缺氧(IH)为特征,与心血管死亡率增加相关,标准治疗可能无法降低心血管死亡率。肾素-血管紧张素-醛固酮系统的不适当激活发生在IH中,矿化皮质激素受体(MR)阻断已被证明可以改善心血管疾病的血管结局。因此,我们假设MR抑制可以防止暴露于慢性IH的小鼠冠状动脉和肾脏血管功能障碍。方法:将人、小鼠冠状动脉血管细胞和雄性C57BL/6J小鼠分别暴露于IH或室内空气(RA)中12小时/天,连续3天(体外)和6周(不给予螺内酯(SPL)或氢氯噻嗪(HTZ)处理。结果:体外研究表明,IH增加了人和小鼠冠状动脉内皮细胞和平滑肌细胞中MR基因的表达。暴露于IH的小鼠血压升高,冠状动脉血流速度储备(CFVR)降低,冠状动脉内皮依赖性扩张减弱,血管收缩剂反应性增强,但肾动脉没有。重要的是,SPL治疗可以预防冠状血管功能的改变,而不依赖于血压,因为HTZ使血压正常化并不能改善CFVR或冠状血管舒缩功能。结论:这些数据表明,慢性IH在体外模拟了中重度OSA的缺氧-再氧循环,增加了冠状动脉MR的表达。它还选择性地促进小鼠冠状动脉血管功能障碍。重要的是,这种功能障碍对SPL的MR拮抗剂敏感,独立于血压。这些发现表明MR阻断可以作为一种辅助治疗来改善OSA患者的长期心血管预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mineralocorticoid receptor antagonism prevents coronary microvascular dysfunction in intermittent hypoxia independent of blood pressure.

Study objectives: Obstructive sleep apnea (OSA), is characterized by intermittent hypoxia (IH), and is associated with increased cardiovascular mortality that may not be reduced by standard therapies. Inappropriate activation of the renin-angiotensin-aldosterone system occurs in IH, and mineralocorticoid receptor (MR) blockade has been shown to improve vascular outcomes in cardiovascular disease. Thus, we hypothesized that MR inhibition prevents coronary and renal vascular dysfunction in mice exposed to chronic IH.

Methods: Human and mouse coronary vascular cells and male C57BL/6J mice were exposed to IH or room air (RA) for 12 hours/day for 3 days (in vitro) and 6 weeks with or without treatments with spironolactone (SPL) or hydrochlorothiazide (HTZ).

Results: In vitro studies demonstrated that IH increased MR gene expression in human and mouse coronary artery endothelial and smooth muscle cells. Exposure to IH in mice increased blood pressure, reduced coronary flow velocity reserve (CFVR), attenuated endothelium-dependent dilation, and enhanced vasoconstrictor responsiveness in coronary, but not renal arteries. Importantly, SPL treatment prevented altered coronary vascular function independent of blood pressure as normalization of BP with HTZ did not improve CFVR or coronary vasomotor function.

Conclusions: These data demonstrate that chronic IH, which mimics the hypoxia-reoxygenation cycles of moderate-to-severe OSA, increases coronary vascular MR expression in vitro. It also selectively promotes coronary vascular dysfunction in mice. Importantly, this dysfunction is sensitive to MR antagonism by SPL, independent of blood pressure. These findings suggest that MR blockade could serve as an adjuvant therapy to improve long-term cardiovascular outcomes in patients with OSA.

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来源期刊
Sleep
Sleep Medicine-Neurology (clinical)
CiteScore
8.70
自引率
10.70%
发文量
0
期刊介绍: SLEEP® publishes findings from studies conducted at any level of analysis, including: Genes Molecules Cells Physiology Neural systems and circuits Behavior and cognition Self-report SLEEP® publishes articles that use a wide variety of scientific approaches and address a broad range of topics. These may include, but are not limited to: Basic and neuroscience studies of sleep and circadian mechanisms In vitro and animal models of sleep, circadian rhythms, and human disorders Pre-clinical human investigations, including the measurement and manipulation of sleep and circadian rhythms Studies in clinical or population samples. These may address factors influencing sleep and circadian rhythms (e.g., development and aging, and social and environmental influences) and relationships between sleep, circadian rhythms, health, and disease Clinical trials, epidemiology studies, implementation, and dissemination research.
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