Coronary artery dysfunction in OSA: Role of mineralocorticoid receptors

OSA 中的冠状动脉功能障碍：盐皮质激素受体的作用

基本信息

批准号：
10734658
负责人：
Mohammad Badran
金额：
$ 67.5万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734658
关键词：
Acceleration Adjuvant Therapy Air Aldosterone Animals Area Atherosclerosis Blood Blood Pressure Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular system Cells Chronic Clinical Trials Collagen Fiber Continuous Positive Airway Pressure Coronary Coronary Vessels Coronary artery Coronary heart disease Data Echocardiography Endothelial Cells Endothelium Euthanasia Exposure to Fasting Fatty acid glycerol esters Female Functional disorder Goals Heart Hour Human Hypertension Hypoxia Impairment Incidence Inflammation Left Link Lipids Mediating Metabolic Methods Microvascular Dysfunction Mineralocorticoid Receptor Molecular Morbidity - disease rate Mus Myocardial Infarction Non obese Obese Mice Obesity Obstructive Sleep Apnea Outcome Oxidative Stress Patients Persons Placebos Play Population Process Protocols documentation Receptor Activation Receptor Inhibition Receptor Signaling Recovery Renin-Angiotensin-Aldosterone System Rest Risk Role Signal Transduction Sleep Sleep Apnea Syndromes Smooth Muscle Myocytes Source Spironolactone System Tail Telemetry Testing Therapeutic Intervention Thinness Tissues Transgenic Mice Treatment Efficacy Vascular Diseases antagonist blood pressure reduction cardiovascular risk factor clinically significant diet-induced obesity dietary control endothelial dysfunction experimental study gene network heart function improved improved outcome in vivo indexing innovation insight insulin tolerance intimal medial thickening male mortality mouse model new therapeutic target normoxia novel obese person prevent receptor sex single nucleus RNA-sequencing therapeutic target therapy development treatment adherence vascular contributions

项目摘要

Abstract Obstructive sleep apnea (OSA) is a prevalent condition worldwide, especially in people with obesity, and is an independent risk factor for cardiovascular disease (CVD), including coronary microvascular dysfunction (CMD). Current available OSA treatments have not consistently detected the anticipated improvements in CVD and CMD, suggesting the need for adjuvant therapies aimed at the mechanisms underlying the core disturbances induced by OSA. As such, OSA-induced renin-angiotensin-aldosterone system (RAAS) activation may trigger excessive mineralocorticoid receptor (MR) signaling, which play a major role in endothelial dysfunction and atherosclerosis. Thus, the hypothesis is that OSA-induced CMD is mediated, at least in part, by MR dependent mechanisms. To examine the role of MR in OSA-induced CMD, obese C57Bl/6 male and female mice will be exposed to intermittent hypoxia (IH) during the rest period, a mouse model of OSA, for 6 weeks (short-term) and 16 weeks (long-term) and treated with the conventional steroidal MR antagonist (spironolactone) or the novel non-steroidal MR antagonist (finerenone) to evaluate the MR-dependent reversibility of IH-induced CMD (SA1). To investigate whether MR inhibition can accelerate CMD recovery, mice will be exposed to short-and long-term IH followed by 12 weeks of normoxia (IH cessation – simulating ideal OSA treatment) with or without concurrent treatment with MR antagonists (SA2). To examine the role of vascular cell-specific MR, transgenic mice with endothelial cell (EC)-specific and smooth muscle cell (SMC)-specific deletions of MR will be exposed to long- term IH (SA3). Coronary artery function will be evaluated in vivo and ex vivo in addition to heart function, blood pressure and metabolic assessments. Moreover, immunohistological analysis of the coronary vessels, along with gene networks expression dynamics among different coronary artery cell populations will be evaluated using single-nucleus RNA sequencing (snRNA-seq). Male and female mice will be fed a high-fat or control diet for 8 weeks then housed in environmental chambers for IH exposures (alternating 6.1% FIO2/21.0%FIO2 90 sec:90 sec, for 6 or 16 weeks during 12 daylight hours, and treated with spironolactone (20mg/kg), finerenone (1mg/kg), or placebo. IH cessation protocol consists of removing the exposed animals for the IH chambers and left under normoxic conditions for 12 weeks. Heart function will be examined via echocardiography, while blood pressure and coronary flow reserve velocity (CFVR) will be assessed using tail cuff method/telemetry and doppler flow velocity system, respectively. Additionally, Insulin tolerance test and fasting blood and lipid profiles will be evaluated. After euthanasia, coronary arteries will be excised and mounted on a wire myograph for functional studies or processed for immunohistological analyses (including intima-media thickness, collagen fiber distribution, and indices of oxidative stress and inflammation) or snRNA-seq. The proposed studies will elucidate the role of MR signaling in OSA-mediated coronary artery dysfunction and potential approaches to enhance CMD reversibility, thereby enabling MR antagonists as biologically plausible therapeutic targets in OSA patients.

抽象的阻塞性睡眠呼吸暂停（OSA）在全球范围很普遍，尤其是在肥胖者中，是一个心血管疾病（CVD）的独立危险因素，包括冠状动脉微血管功能障碍（CMD）。当前可用的OSA治疗尚未始终检测到CVD的预期改善和 CMD，表明需要调整针对核心灾难基础机制的疗法由OSA诱导。因此，OSA诱导的肾素 - 血管紧张素 - 醛固酮系统（RAAS）激活可能会触发过多的矿物皮质受体（MR）信号传导，在内皮功能障碍和动脉粥样硬化。这是假设的是，OSA诱导的CMD至少部分由MR依赖性介导机制。为了检查MR在OSA诱导的CMD中的作用，肥胖的C57BL/6雄性和雌性小鼠将是在剩下期间暴露于间歇性缺氧（IH），OSA的小鼠模型，持续6周（短期）和 16周（长期），并用常规类固醇MR拮抗剂（螺内酯）或新颖非甾体类MR拮抗剂（Finerenone）评估IH诱导的CMD（SA1）的MR依赖性可逆性。为了调查MR抑制是否可以加速CMD恢复，小鼠将暴露于短期和长期 IH随后进行12周的正常氧（IH停止 - 模拟理想的OSA治疗），有或不同时用MR拮抗剂治疗（SA2）。检查血管细胞特异性MR的作用，转基因小鼠与内皮细胞（EC）特异性和平滑肌细胞（SMC）MR的特异性缺失将暴露于长期术语IH（SA3）。除心脏功能外，还将在体内和体内评估冠状动脉功能压力和代谢评估。此外，对冠状血管的免疫组织学分析沿使用基因网络的表达动力学在不同的冠状动脉细胞种群之间进行评估单核RNA测序（SnRNA-Seq）。雄性和雌性小鼠将获得高脂或控制饮食的8 然后在环境室中安置了IH暴露（交替的6.1％FIO2/21.0％Fio2 90秒：90） SEC，在12个白天的时间内持续6或16周，并用螺内酯（20mg/kg），罚款（1mg/kg）治疗或安慰剂。 IH戒烟协议包括去除IH腔室的暴露动物，然后留在下面常氧条件12周。心脏功能将通过超声心动图检查，而血压将使用尾袖方法/遥测和多普勒流量评估冠状动脉储备速度（CFVR）速度系统。此外，胰岛素耐受性测试以及禁食的血液和脂质特征将是评估。安乐死之后，冠状动脉将非常出色，并安装在电线肌电图上以进行功能研究或处理免疫组织学分析（包括内膜膜厚度，胶原蛋白纤维氧化应激和炎症的分布和指标）或snRNA-seq。拟议的研究将阐明 MR信号在OSA介导的冠状动脉功能障碍和增强潜在方法中的作用 CMD可逆性，从而使MR拮抗剂成为OSA患者的生物学上合理的治疗靶标。