Institute for Vascular Signalling, Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany.
Cardiovasc Res. 2010 Jan 1;85(1):232-40. doi: 10.1093/cvr/cvp281.
The C-terminal domain of the soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active diols, while the N-terminal domain demonstrates lipid phosphatase activity. As EETs are potent vasoconstrictors in the pulmonary circulation, we assessed the development of pulmonary hypertension induced by exposure to hypoxia (10% O(2)) for 21 days in wild-type (WT) and sEH(-/-) mice and compared the effects with chronic (4 months) sEH inhibition.
In isolated lungs from WT mice, acute hypoxic vasoconstriction (HPV) was potentiated by sEH inhibition and attenuated by an EET antagonist. After prolonged hypoxia, the acute HPV and sensitivity to the EET antagonist were increased, but potentiation of vasoconstriction following sEH inhibition was not evident. Chronic hypoxia also stimulated the muscularization of pulmonary arteries and decreased sEH expression in WT mice. In normoxic sEH(-/-) mice, acute HPV and small artery muscularization were greater than that in WT lungs and enhanced muscularization was accompanied with decreased voluntary exercise capacity. Acute HPV in sEH(-/-) mice was insensitive to sEH inhibition but inhibited by the EET antagonist and chronic hypoxia induced an exaggerated pulmonary vascular remodelling. In WT mice, chronic sEH inhibition increased serum EET levels but failed to affect acute HPV, right ventricle weight, pulmonary artery muscularization, or voluntary running distance. In human donor lungs, the sEH was expressed in the wall of pulmonary arteries, however, sEH expression was absent in samples from patients with pulmonary hypertension.
These data suggest that a decrease in sEH expression is intimately linked to pathophysiology of hypoxia-induced pulmonary remodelling and hypertension. However, as sEH inhibitors do not promote the development of pulmonary hypertension it seems likely that the N-terminal lipid phosphatase may play a role in the development of this disease.
可溶性环氧化物水解酶（sEH）的 C 端结构域将环氧二十碳三烯酸（EETs）代谢为其活性较低的二醇，而 N 端结构域则表现出脂质磷酸酶活性。由于 EETs 是肺循环中强有力的血管收缩剂，我们评估了在野生型（WT）和 sEH（-/-）小鼠中暴露于低氧（10% O（2））21 天后引起的肺动脉高压的发展，并将其与慢性（4 个月）sEH 抑制进行了比较。
在 WT 小鼠的离体肺中，急性低氧性血管收缩（HPV）被 sEH 抑制增强，而被 EET 拮抗剂减弱。经过长时间的低氧后，急性 HPV 和对 EET 拮抗剂的敏感性增加，但 sEH 抑制后血管收缩的增强并不明显。慢性低氧也刺激了肺动脉的肌化并降低了 WT 小鼠中 sEH 的表达。在常氧 sEH（-/-）小鼠中，急性 HPV 和小动脉肌化大于 WT 肺，并且增强的肌化伴随着自愿运动能力的降低。sEH（-/-）小鼠中的急性 HPV 对 sEH 抑制不敏感，但对 EET 拮抗剂和慢性低氧抑制敏感，慢性低氧诱导了肺动脉血管重塑的过度表达。在 WT 小鼠中，慢性 sEH 抑制增加了血清 EET 水平，但对急性 HPV、右心室重量、肺动脉肌化或自愿跑步距离没有影响。在人类供体肺中，sEH 表达于肺动脉壁，但在肺动脉高压患者的样本中，sEH 表达缺失。
这些数据表明，sEH 表达的降低与低氧诱导的肺重塑和高血压的病理生理学密切相关。然而，由于 sEH 抑制剂不会促进肺动脉高压的发展，因此 N 端脂质磷酸酶可能在该疾病的发展中起作用。
