Institute of Physiology II, University of Münster, Münster, Germany.
FASEB J. 2013 Sep;27(9):3652-9. doi: 10.1096/fj.13-228312. Epub 2013 May 31.
Aldosterone triggers the stiff endothelial cell syndrome (SECS), characterized by an up-regulation of epithelial sodium channels (ENaCs) and mechanical stiffening of the endothelial cell cortex accompanied by endothelial dysfunction. In vivo, aldosterone antagonism exerts sustained protection on the cardiovascular system. To illuminate the molecular mechanisms of this time-dependent effect, a study on endothelial cells in vitro and ex vivo was designed to investigate SECS over time. Endothelia (from human umbilical veins, bovine aortae, and explants of human arteries) were cultured in aldosterone-supplemented medium with or without the mineralocorticoid receptor (MR) antagonist spironolactone. MR expression, ENaC expression, cortical stiffness, and shear-mediated nitric oxide (NO) release were determined after 3 d (short term) and up to 24 d (long term). Over time, MR expression increased by 129%. ENaC expression and surface abundance increased by 32% and 42% (13.8 to 19.6 molecules per cell surface), paralleled by a 49% rise in stiffness. Spironolactone prevented this development and, after 3 wk of treatment, increased NO release by 50%. Thus, spironolactone improves endothelial function long-lastingly by preventing a time-dependent manifestation of SECS. This emphasizes the key role of vascular endothelium as a therapeutical target in cardiovascular disorders and might explain blood pressure independent actions of MR antagonism.
醛固酮引发硬内皮细胞综合征（SECS），其特征是上皮钠通道（ENaC）上调和内皮细胞皮质机械僵硬，伴有内皮功能障碍。在体内，醛固酮拮抗作用对心血管系统持续发挥保护作用。为了阐明这种时相关作用的分子机制，设计了一项体外和离体的内皮细胞研究，以随时间研究 SECS。将内皮细胞（来自人脐静脉、牛主动脉和人动脉外植体）在补充有醛固酮的培养基中培养，其中含有或不含有盐皮质激素受体（MR）拮抗剂螺内酯。在 3 天（短期）和长达 24 天（长期）后，测定 MR 表达、ENaC 表达、皮质硬度和剪切介导的一氧化氮（NO）释放。随着时间的推移，MR 表达增加了 129%。ENaC 表达和表面丰度增加了 32%和 42%（每个细胞表面 13.8 到 19.6 个分子），同时硬度增加了 49%。螺内酯可预防这种情况的发生，并且在治疗 3 周后，NO 释放增加了 50%。因此，螺内酯通过预防 SECS 的时间依赖性表现，可长期改善内皮功能。这强调了血管内皮作为心血管疾病治疗靶点的关键作用，并且可能解释了 MR 拮抗作用的血压独立作用。
