From the Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa.
Hypertension. 2018 Nov;72(5):1227-1235. doi: 10.1161/HYPERTENSIONAHA.118.11857.
Low-salt diet is beneficial in salt-sensitive hypertension but may provoke cardiovascular risk in patients with heart failure, diabetes mellitus, or other cardiovascular abnormalities because of endogenous renin-angiotensin system activation. PPAR (peroxisome proliferator-activated receptor)-γ is a transcription factor which promotes an antioxidant pathway in the endothelium. We studied transgenic mice expressing a dominant-negative mutation in PPAR-γ selectively in the endothelium (E-V290M) to test the hypothesis that endothelial PPAR-γ plays a protective role in response to low salt-mediated renin-angiotensin system activation. Plasma renin and Ang II (angiotensin II) were significantly and equally increased in all mice fed low salt for 6 weeks. Vasorelaxation to acetylcholine was not affected in basilar artery from E-V290M at baseline but was significantly and selectively impaired in E-V290M after low salt. Unlike basilar artery, low salt was not sufficient to induce vascular dysfunction in carotid artery or aorta. Endothelial dysfunction in the basilar artery from E-V290M mice fed low salt was attenuated by scavengers of superoxide, inhibitors of NADPH oxidase, or blockade of the Ang II AT1 (angiotensin type-1) receptor. Simultaneous AT1 and AT2 receptor blockade revealed that the restoration of endothelial function after AT1 receptor blockade was not a consequence of AT2 receptor activation. We conclude that interference with PPAR-γ in the endothelium produces endothelial dysfunction in the cerebral circulation in response to low salt-mediated activation of the endogenous renin-angiotensin system, mediated at least in part, through AT1 receptor activation and perturbed redox homeostasis. Moreover, our data suggest that the cerebral circulation may be particularly sensitive to inhibition of PPAR-γ activity and renin-angiotensin system activation.
低盐饮食有益于盐敏感型高血压，但可能会在心力衰竭、糖尿病或其他心血管异常患者中引发心血管风险，这是由于内源性肾素-血管紧张素系统的激活。PPAR（过氧化物酶体增殖物激活受体）-γ 是一种转录因子，可促进内皮细胞中的抗氧化途径。我们研究了在血管内皮细胞中选择性表达 PPAR-γ 显性负突变的转基因小鼠（E-V290M），以检验内皮细胞 PPAR-γ 在响应低盐介导的肾素-血管紧张素系统激活中发挥保护作用的假说。所有低盐喂养 6 周的小鼠的血浆肾素和 Ang II（血管紧张素 II）均显著且同等增加。E-V290M 小鼠基底动脉的乙酰胆碱介导的血管舒张在基线时不受影响，但在低盐后则显著且选择性受损。与基底动脉不同，低盐不足以引起颈动脉或主动脉的血管功能障碍。E-V290M 小鼠低盐喂养的基底动脉内皮功能障碍可被超氧化物清除剂、NADPH 氧化酶抑制剂或 Ang II AT1（血管紧张素 1 型）受体阻断剂减弱。同时阻断 AT1 和 AT2 受体表明，AT1 受体阻断后内皮功能的恢复不是 AT2 受体激活的结果。我们得出结论，内皮细胞中 PPAR-γ 的干扰会导致内源性肾素-血管紧张素系统激活引起的脑循环内皮功能障碍，至少部分通过 AT1 受体激活和氧化还原平衡失调介导。此外，我们的数据表明，脑循环可能对 PPAR-γ 活性和肾素-血管紧张素系统激活的抑制特别敏感。
