Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Eur Heart J. 2013 Dec;34(45):3515-24. doi: 10.1093/eurheartj/eht095. Epub 2013 Apr 17.
Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.
C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.
Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.
醛固酮在心血管疾病中起着至关重要的作用。其矿物质皮质激素受体 (MR) 的“系统性”抑制通过减少炎症和氧化应激来降低动脉粥样硬化。肥胖是一种重要的心血管危险因素，是一种与血浆醛固酮水平升高相关的炎症性疾病。我们研究了“内皮”MR 在肥胖引起的内皮功能障碍中的作用，这是动脉粥样硬化形成的最早阶段。
C57BL/6 小鼠暴露于正常饲料（ND）或高脂肪饮食（HFD）单独或与 MR 拮抗剂依普利酮（200mg/kg/天）联合治疗 14 周。饮食诱导的肥胖损害了对乙酰胆碱的内皮依赖性舒张反应，而依普利酮治疗肥胖小鼠可预防这种情况。从这些小鼠分离的主动脉内皮细胞的表达分析表明，依普利酮减弱了氧化应激 NADPH 氧化酶（亚基 p22phox、p40phox）的表达，并增加了抗氧化基因（谷胱甘肽过氧化物酶-1、超氧化物歧化酶-1 和 -3）的表达。依普利酮不影响肥胖诱导的环氧合酶 (COX)-1 或前列环素合酶的上调。内皮特异性 MR 缺失可防止肥胖（表现出高“内源性”醛固酮）和“外源性”醛固酮输注瘦小鼠的内皮功能障碍。预先用 COX 抑制剂吲哚美辛孵育来自醛固酮处理动物的主动脉环可恢复内皮功能。在外皮 MR 存在的情况下，而不是不存在的情况下，外源性醛固酮给药诱导内皮表达 p22phox。
肥胖诱导的内皮功能障碍依赖于“内皮”MR，并由氧化应激调节机制的失衡介导。因此，MR 拮抗剂可能代表一种有吸引力的治疗策略，用于增加肥胖患者的人群，以减少血管功能障碍和随后的动脉粥样硬化并发症。
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