Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling.
Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling.
复制标题
DOI：
10.1152/ajplung.00345.2016
复制
发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Mathew J. Wong;Crystal Kantores;J. Ivanovska;Amish Jain;R. Jankov
中科院分区：
文献类型：
--
作者：
Mathew J. Wong;Crystal Kantores;J. Ivanovska;Amish Jain;R. Jankov
慢性新生儿肺动脉高压（PHT）经常导致早期死亡。全身给予Rho激酶（ROCK）抑制剂可预防和逆转新生大鼠的慢性PHT，但代价是严重的不良反应，包括全身性低血压和生长受限。辛伐他汀对类异戊二烯中间体具有多效性抑制作用，这可能限制ROCK上游信号传导的RhoA的活性。因此，我们假设他汀类药物治疗可以安全地限制肺血管RhoA活性，并通过对病理性ROCK活性的下游抑制作用预防和逆转实验性慢性新生儿PHT。在常氧（室内空气）或中度常压缺氧（13%O2）的Sprague-Dawley大鼠中，从出生后第1-14天（预防方案）或第14-21天（挽救方案）接受辛伐他汀（2 mg·kg-1·day-1 ip）或溶剂。慢性缺氧可增加肺组织RhoA和ROCK活性。辛伐他汀减少了类异戊二烯中间体焦磷酸法呢酯的肺含量，并减少了缺氧暴露肺中的RhoA/ROCK信号传导。辛伐他汀对慢性低氧暴露动物的预防性或补救性治疗可降低肺血管阻力、右心室肥大和肺动脉重构。预防性辛伐他汀治疗改善了体重增加，没有降低全身血压，也没有对骨骼肌、肝脏或大脑造成明显的毒性作用。辛伐他汀补救治疗可改善运动能力。我们的结论是，辛伐他汀限制RhoA/ROCK活性在慢性缺氧暴露的肺，从而防止或改善慢性PHT的血流动力学和结构标志物，并改善长期结果，而不会引起不良反应。
Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity. Sprague-Dawley rats in normoxia (room air) or moderate normobaric hypoxia (13% O2) received simvastatin (2 mg·kg-1·day-1 ip) or vehicle from postnatal days 1-14 (prevention protocol) or from days 14-21 (rescue protocol). Chronic hypoxia increased RhoA and ROCK activity in lung tissue. Simvastatin reduced lung content of the isoprenoid intermediate farnesyl pyrophosphate and decreased RhoA/ROCK signaling in the hypoxia-exposed lung. Preventive or rescue treatment of chronic hypoxia-exposed animals with simvastatin decreased pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary arterial remodeling. Preventive simvastatin treatment improved weight gain, did not lower systemic blood pressure, and did not cause apparent toxic effects on skeletal muscle, liver or brain. Rescue therapy with simvastatin improved exercise capacity. We conclude that simvastatin limits RhoA/ROCK activity in the chronic hypoxia-exposed lung, thus preventing or ameliorating hemodynamic and structural markers of chronic PHT and improving long-term outcome, without causing adverse effects.