From the Diabetes and Cardiovascular Research Center (G.J., J.H., A.R.A., A.W.-C., J.R.S.).
Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, Columbia, MO (G.J., J.H., A.R.A., A.W.-C., J.R.S.).
Hypertension. 2018 Sep;72(3):731-738. doi: 10.1161/HYPERTENSIONAHA.118.11339.
Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously, we showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the α-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an epithelial sodium channel antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that endothelial cell-specific EnNaC activation is necessary for aldosterone-mediated endothelium stiffness. To address this notion, EnNaC α-subunit knockout (EnNaC) and wild-type littermate female mice were administrated aldosterone (250 µg/kg per day) via osmotic minipumps for 3 weeks beginning at 25 to 28 weeks of age. In isolated mouse endothelial cells, inward sodium currents were significantly reduced in amiloride controls, as well as in EnNaC. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium-dependent relaxation less in EnNaC versus wild-type. Further, EnNaC mice exhibited attenuated responses to aldosterone infusion, including aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of proinflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that αEnNaC subunit activation contributes to these vascular responses.
内皮矿物ocorticoid 受体的激活增强导致动脉僵硬的发展，动脉僵硬是心血管疾病的独立预测因子。此前，我们发现雌性小鼠内皮矿物ocorticoid 受体信号的增强促使上皮钠通道的α亚单位表达和易位到内皮细胞（EC）表面（EnNaC），从而诱导血管纤维化和僵硬。此外，上皮钠通道拮抗剂阿米洛利可抑制富含饱和脂肪和精制碳水化合物的西方饮食诱导的血管纤维化、重塑和僵硬。然而，这是如何发生的仍不清楚。因此，我们假设内皮细胞特异性 EnNaC 的激活对于醛固酮介导的内皮僵硬是必需的。为了验证这一观点，我们对 EnNaCα亚单位敲除（EnNaC）和野生型同窝雌性小鼠进行了醛固酮（每天 250μg/kg）经渗透微型泵给药，从 25 到 28 周龄开始给药 3 周。在分离的小鼠内皮细胞中，阿米洛利对照以及 EnNaC 均显著降低内向钠电流。同样，与野生型相比，EnNaC 中的醛固酮诱导的内皮僵硬增加，内皮依赖性松弛减少。此外，EnNaC 小鼠对醛固酮输注的反应减弱，包括主动脉内质网应激、内皮型一氧化氮合酶激活、内皮通透性、促炎细胞因子表达、氧化应激和主动脉胶原 1 沉积，这支持了αEnNaC 亚单位激活有助于这些血管反应的观点。
