Department of Physiology.
Hebei Key Laboratory of Animal Science, Hebei Medical University, Shijiazhuang.
J Hypertens. 2018 Mar;36(3):651-665. doi: 10.1097/HJH.0000000000001605.
We aimed to elucidate the ameliorative effect of hydrogen sulfide (H2S) on endothelium-dependent relaxation disturbances via peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase (PPARδ/eNOS) pathway activation in hypertensive patients and rats.
Renal arteries were collected from normotensive and hypertensive patients who underwent nephron-sparing surgery. Renal arteries from 37 patients were cultured with or without sodium H2S (NaHS) 50 μmol/l. The rats were randomly divided into four groups: Sham; Sham + NaHS, two kidneys; one clipped (2K1C); and 2K1C + NaHS. Mean arterial pressure was measured by tail-cuff plethysmography. A microvessel recording technique was used to observe the effect of NaHS on endothelium-dependent relaxation. Plasma H2S concentrations were detected using the monobromobimane method. Real-time PCR and western blotting were used to assess mRNA and protein levels of AT1, cystathionine γ-lyase, PPARδ, and phosphor-eNOS. Laser confocal scanning microscopy measured intracellular NO production in human umbilical vein endothelial cells.
NaHS improved endothelial function in hypertensive humans and rats. The 20-week administration of NaHS to 2K1C rats lowered the mean arterial pressure. In human umbilical vein endothelial cells, NaHS improved the AngII-induced production of NO. NaHS upregulated PPARδ expression, increased protein kinase B (Akt) or adenosine monophosphate kinase-activated protein kinase (AMPK) phosphorylation, and enhanced eNOS phosphorylation. A PPARδ agonist could mimic the ameliorative effect of NaHS that was suppressed by PPARδ, AMPK, or Akt inhibition.
H2S plays a protective function in renal arterial endothelium in hypertension by activating the PPARδ/PI3K/Akt/eNOS or PPARδ/AMPK/eNOS pathway. H2S may serve as an effective strategy against hypertension.
本研究旨在阐明硫化氢（H2S）通过激活过氧化物酶体增殖物激活受体δ/内皮型一氧化氮合酶（PPARδ/eNOS）通路对高血压患者和大鼠内皮依赖性舒张功能障碍的改善作用。
从接受保肾手术的正常血压和高血压患者中采集肾动脉。将 37 名患者的肾动脉与或不与 50μmol/l 的 NaHS 孵育。将大鼠随机分为四组：假手术组；假手术+NaHS 组，双肾；两肾一夹（2K1C）组；2K1C+NaHS 组。通过尾套测压法测量平均动脉压。使用微血管记录技术观察 NaHS 对内皮依赖性舒张的影响。使用单溴化脒法检测血浆 H2S 浓度。实时 PCR 和 Western blot 用于评估 AT1、胱硫醚γ-裂解酶、PPARδ 和磷酸化 eNOS 的 mRNA 和蛋白水平。激光共聚焦扫描显微镜测量人脐静脉内皮细胞内的 NO 产生。
NaHS 改善了高血压患者和大鼠的内皮功能。20 周给予 2K1C 大鼠 NaHS 可降低平均动脉压。在人脐静脉内皮细胞中，NaHS 改善了 AngII 诱导的 NO 产生。NaHS 上调 PPARδ 表达，增加蛋白激酶 B（Akt）或腺苷单磷酸激酶激活的蛋白激酶（AMPK）磷酸化，并增强 eNOS 磷酸化。PPARδ 激动剂可模拟 NaHS 的改善作用，而 PPARδ、AMPK 或 Akt 抑制可抑制该作用。
H2S 通过激活 PPARδ/PI3K/Akt/eNOS 或 PPARδ/AMPK/eNOS 通路在高血压肾动脉内皮中发挥保护作用。H2S 可能是治疗高血压的有效策略。
