Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, Scotland, UK.
Am J Respir Cell Mol Biol. 2012 Aug;47(2):140-8. doi: 10.1165/rcmb.2011-0411OC. Epub 2012 Mar 1.
Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling. We previously showed that acute hypoxic pulmonary adventitial fibroblast proliferation can be selectively inhibited by statins and p38 mitogen-activated protein (MAP) kinase inhibitors. Here we used complementary chronic hypoxic and acute hypoxic coculture models to obtain necessary preclinical information regarding the utility of fluvastatin in the treatment of chronic hypoxic pulmonary hypertension. The effects of fluvastatin, cholesterol pathway intermediates, and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation, and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation-specific, and implicated a Rac1-p38 MAP kinase signaling pathway. Coculture and conditioned media experiments also implicated this statin-sensitive signaling pathway in the release of pulmonary artery smooth muscle cell mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil, and bosentan exerted no effect on the hypoxic fibroblast phenotype. Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts during chronic hypoxia are dependent on a Rac1-p38 MAP kinase signaling pathway. The inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high-altitude residents and in patients with hypoxic lung disease.
低氧性肺动脉高压是一个全球性的公共健康问题。他汀类药物可减轻动物模型中的低氧性肺动脉高压，但作用机制和这些结果在人类治疗中的适用性尚未确定。在低氧模型中，肺动脉成纤维细胞增殖对肺血管重构有重要贡献。我们之前曾表明，他汀类药物和 p38 丝裂原活化蛋白（MAP）激酶抑制剂可选择性抑制急性低氧性肺外膜成纤维细胞增殖。在这里，我们使用互补的慢性低氧和急性低氧共培养模型，获得了氟伐他汀治疗慢性低氧性肺动脉高压的临床前信息。使用互补的慢性低氧大鼠和急性低氧牛细胞模型，确定了氟伐他汀、胆固醇途径中间产物和相关抑制剂对低氧性外膜成纤维细胞增殖、p38 MAP 激酶磷酸化和肺动脉平滑肌细胞增殖的影响。氟伐他汀逆转了慢性低氧动物外膜成纤维细胞的增殖表型转换。这种作用是循环特异性的，并涉及 Rac1-p38 MAP 激酶信号通路。共培养和条件培养基实验也表明，这种他汀类敏感的信号通路参与了低氧性肺外膜成纤维细胞释放肺动脉平滑肌细胞有丝分裂原。曲前列尼尔、西地那非和波生坦对低氧性成纤维细胞表型没有影响。慢性低氧期间肺动脉成纤维细胞的表型变化（增殖增加和有丝分裂原释放）依赖于 Rac1-p38 MAP 激酶信号通路。氟伐他汀抑制这些表型变化可能与高原居民和低氧性肺病患者的治疗有关。
