Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.
Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.
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内皮盐皮质激素受体激活介导饮食引起的肥胖中的内皮功能障碍。
DOI：
10.1093/eurheartj/eht095
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发表时间：
2013-12
影响因子：
39.3
通讯作者：
Matter CM
中科院分区：
文献类型：
--
作者：
Schäfer N;Lohmann C;Winnik S;van Tits LJ;Miranda MX;Vergopoulos A;Ruschitzka F;Nussberger J;Berger S;Lüscher TF;Verrey F;Matter CM
醛固酮在心血管疾病中起着关键作用。“系统性”抑制其矿物皮质激素受体（MR）通过减少炎症和氧化应激来减少动脉粥样硬化。肥胖是一种与血浆醛固酮水平升高相关的炎症性疾病，是重要的心血管危险因素。我们研究了“内皮”磁共振在肥胖诱导的内皮功能障碍中的作用，这是动脉粥样硬化的最早阶段。C57BL/6小鼠单独或联合MR拮抗剂epleenone （200 mg/kg/天）给予正常饮食（ND）或高脂肪饮食（HFD），持续14周。饮食引起的肥胖损害了对乙酰胆碱反应的内皮依赖性松弛，而肥胖小鼠的依普利酮治疗可以防止这种情况。对这些小鼠主动脉内皮细胞的表达分析显示，eplerenone降低了肥胖小鼠中促氧化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化酶(COX)-1或前列环素合成酶的上调。内皮特异性MR缺失可防止肥胖小鼠（表现出高“内源性”醛固酮）和“外源性”醛固酮注入瘦小鼠的内皮功能障碍。用cox -抑制剂吲哚美辛对醛固酮处理的动物的主动脉环进行预孵育，可恢复内皮功能。外源性醛固酮可以诱导内皮细胞p22phox的表达，但在内皮MR不存在的情况下则不会。肥胖诱导的内皮功能障碍取决于“内皮”MR，并由氧化应激调节机制的不平衡介导。因此，MR拮抗剂可能是一种有吸引力的治疗策略，可以减少越来越多的肥胖患者的血管功能障碍和随后的动脉粥样硬化并发症。
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.
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DOI：
10.1161/hypertensionaha.110.161653
发表时间：
2011-03
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Gros R;Ding Q;Sklar LA;Prossnitz EE;Arterburn JB;Chorazyczewski J;Feldman RD
通讯作者：
Feldman RD
影响因子：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
影响因子：
6.9
作者：
Ahima, Rexford S.
通讯作者：
Ahima, Rexford S.
影响因子：
37.8
作者：
Garnier, A;Bendall, JK;Delcayre, C
通讯作者：
Delcayre, C
影响因子：
4.8
作者：
Gomez-Sanchez, CE;de Rodriguez, AF;Gomez-Sanchez, EP
通讯作者：
Gomez-Sanchez, EP