Therapeutic potency of Nrf2, a key antioxidative transcription factor, for pulmonary hypertension

三周的低氧加重了小鼠的肺动脉高压（PH）、右心室肥大（RVH）和肺血管重构。这些病理变化与细胞外糖蛋白腱生蛋白-C的异常积累有关。奥替普拉（一种有效的Nrf 2激活剂）和Keap 1（Nrf 2的负调节因子）敲低均可显著减弱RVH和肺血管重塑，并同时改善缺氧小鼠肺中生腱蛋白-C的蓄积。Nrf 2调节的抗氧化酶的表达降低慢性阻塞性肺疾病与PH相关的患者。抗氧化酶的减少可能是慢性阻塞性肺疾病和PH患者心肺变化的发病机制的基础。奥替普拉的疗效突出了Nrf 2激活剂预防低氧性肺疾病患者PH的有前途的治疗潜力。

Three weeks of hypoxia exacerbated pulmonary hypertension (PH), right ventricular hypertrophy (RVH), and pulmonary vascular remodeling in mice. These pathological changes were associated with aberrant accumulation of a extracellular glycoprotein, Tenascin-C. Both administration of oltipraz, a potent Nrf2 activator, and Keap1 (negative regulator of Nrf2) knockdown significantly attenuated RVH and pulmonary vascular remodeling and concomitantly ameliorated Tenascin-C accumulation in the hypoxic mouse lungs. Expression of the Nrf2-regulated antioxidant enzymes was decreased in a patient with chronic obstructive pulmonary disease associated with PH. The decreased antioxidant enzymes may underlie the pathogenesis of cardiopulmonary changes in the patient with chronic obstructive pulmonary disease and PH. The efficacy of oltipraz highlights a promising therapeutic potency of Nrf2 activators for the prevention of PH in patients with hypoxemic lung disease.