Cardiovascular Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA.
J Cardiovasc Pharmacol. 2011 Aug;58(2):181-91. doi: 10.1097/FJC.0b013e31821f2773.
Hypoxia-induced pulmonary arterial hypertension (PAH) is a deadly disease characterized by progressive remodeling and persistent vasoconstriction of the pulmonary arterial system. Remodeling of the pulmonary artery (PA) involves smooth muscle cell (SMC) proliferation, hypertrophy, migration, and elevated extracellular matrix (ECM) production elicited by mitogens and oxidants produced in response to hypoxic insult. We previously reported that the transcription factor cAMP response element binding protein (CREB) is depleted in medial PA SMCs in remodeled, hypertensive vessels in rats or calves exposed to chronic hypoxia. In culture, CREB loss can be induced in PA SMCs by exogenous oxidants or platelet-derived growth factor. Forced depletion of CREB with small interfering RNA (siRNA) in PA SMCs is sufficient to induce their proliferation, hypertrophy, migration, dedifferentiation, and ECM production. This suggests that oxidant and/or mitogen-induced loss of CREB in medial SMCs is, in part, responsible for PA thickening. Here, we tested whether oxidant scavengers could prevent the loss of CREB in PA SMCs and inhibit SMC proliferation, migration, and ECM production using in vitro and in vivo models. Exposure of PA SMCs to hypoxia induced hydrogen peroxide (H2O2) production and loss of CREB. Treatment of SMCs with exogenous H2O2 or a second oxidant, Sin-1, elicited CREB depletion under normoxic conditions. Exogenous H2O2 also induced SMC proliferation, migration, and increased elastin levels as did forced depletion of CREB. In vivo, hypoxia-induced thickening of the PA wall was suppressed by the superoxide dismutase mimetic, Tempol, which also prevented the loss of CREB in medial SMCs. Tempol also reduced hypoxia-induced SMC proliferation and elastin deposition in the PA. The data indicate that CREB levels in the arterial wall are regulated in part by oxidants produced in response to hypoxia and that CREB plays a crucial role in regulating SMC phenotype and PA remodeling.
低氧诱导性肺动脉高压（PAH）是一种致命性疾病，其特征为肺动脉系统进行性重塑和持续收缩。肺动脉（PA）重塑涉及平滑肌细胞（SMC）增殖、肥大、迁移以及细胞外基质（ECM）的产生增加，这些都是对缺氧损伤的有丝分裂原和氧化剂反应的结果。我们之前报道过，在慢性低氧暴露的大鼠或小牛的重塑性高血压血管中，中层 PA SMC 中的转录因子 cAMP 反应元件结合蛋白（CREB）耗竭。在培养中，外源性氧化剂或血小板衍生生长因子可诱导 PA SMC 中 CREB 的丧失。PA SMC 中 CREB 的小干扰 RNA（siRNA）强制耗竭足以诱导其增殖、肥大、迁移、去分化和 ECM 产生。这表明，氧化应激和/或有丝分裂原诱导的中层 SMC 中 CREB 的丧失部分是 PA 增厚的原因。在这里，我们使用体外和体内模型来测试氧化剂清除剂是否可以防止 PA SMC 中 CREB 的丧失并抑制 SMC 的增殖、迁移和 ECM 产生。PA SMC 暴露于低氧可诱导过氧化氢（H2O2）的产生和 CREB 的丧失。在常氧条件下，用外源性 H2O2 或第二种氧化剂 Sin-1 处理 SMC 可引发 CREB 耗竭。外源性 H2O2 还诱导 SMC 增殖、迁移并增加弹性蛋白水平，如 CREB 强制耗竭一样。在体内，超氧化物歧化酶类似物 Tempol 抑制缺氧诱导的 PA 壁增厚，这也可防止中层 SMC 中 CREB 的丧失。Tempol 还减少了缺氧诱导的 SMC 增殖和 PA 中的弹性蛋白沉积。数据表明，动脉壁中 CREB 水平部分受缺氧反应产生的氧化剂调节，并且 CREB 在调节 SMC 表型和 PA 重塑中起着关键作用。
