黄军霞　李颖　范玉华　涂应锋

[摘要] 目的 探討阿托伐他汀钙（ATV）对野百合碱诱导的肺动脉平滑肌细胞（PASMCs）增殖与凋亡作用及其分子机制。 方法 将PASMCs随机分为对照组、野百合碱组、野百合碱+ATV组以及野百合碱+ATV+SC79组。应用MTT法检测PASMCs细胞的生长情况，荧光TUNEL法分析PASMCs细胞凋亡情况，并用免疫印迹法检测PASMCs细胞中PI3K、AKT、p-AKT、Bcl-2以及Bax表达的变化。 结果 与对照组比较，野百合碱组PASMCs细胞增殖明显增强（P < 0.01），ATV能明显抑制MCT诱导的PASMCs细胞增殖（P < 0.01），且ATV可明显降低PI3K/AKT通路蛋白及Bcl-2蛋白的表达，而升高Bax蛋白的表达，诱导PASMCs细胞凋亡（P < 0.01）。此外，AKT特异性激动剂SC79能逆转ATV的作用。 结论 ATV通过作用于PI3K/AKT信号通路调控PASMCs细胞增殖，诱导细胞凋亡，为肺动脉高压治疗提供新的治疗策略。

[关键词] 肺动脉高压；阿托伐他汀钙；野百合碱；PI3K/AKT；凋亡

[中图分类号] R543.204 [文献标识码] A [文章编号] 1673-7210（2016）12（a）-0008-05

Effect of Atorvastatin Calcium on the proliferation and apoptosis of monocrotaline-induced pulmonary artery smooth muscle cells

HUANG Junxia1 LI Ying2 FAN Yuhua3 TU Yingfeng4▲

1.The Third Department of Internal Medicine， Kaihua People's Hospital of Quzhou City， Zhejiang Province， Kaihua 324300， China； 2.the Second Department of Internal Medicine， Kaihua People's Hospital of Quzhou City， Zhejiang Province， Kaihua 324300， China； 3.College of Pharmacy， Harbin Medical University， Heilongjiang Province， Daqing 163000， China； 4.Department of Cardiology， the Fourth Hospital Affiliated to Harbin Medical University， Heilongjiang Province， Daqing 150001， China

[Abstract] Objective To investigate the effects and molecular mechanism of Atorvastatin Calcium （ATV） on the proliferation and apoptosis of pulmonary artery smooth muscle cells （PASMCs） induced by monocrotaline. Methods The PASMCs were randomly assigned into four groups： control group， monocrotaline group， monocrotaline+ATV group and monocrotaline+ATV+SC79 group. The MTT assay was used to assess the proliferation of PASMCs cells. And the PASMCs apoptosis was analyzed by TUNEl apoptosis assay kit. Furthermore， the expression of PI3K， AKT， p-AKT， Bcl-2 and Bax was determined by the Western blot assay. Results Compared with control group， the proliferation of PASMCs was obviously increased in monocrotaline group （P < 0.01）， while the ATV could inhibit the effect of monocrotaline in PASMCs （P < 0.01）， in addition， the expression of PI3K/AKT signal proteins and Bcl-2 protein in monocrotaline+ATV treated PASMCs cells were decreased significantly， while the expression of Bax was increased significantly， and ATV could induce apoptosis in PASMCs （P < 0.01）. However， the SC79， a unique specific AKT activator， could reverse the effect of ATV on PASMCs. Conclusion ATC has protective effects on the proliferation and apoptosis of pulmonary artery smooth muscle cells via PI3K/AKT signal pathway， which might be a novel strategy for treating pulmonary artery hypertension.

[Key words] Pulmonary artery hypertension； Atorvastatin Calcium； Monocrotaline； PI3K/AKT； Apoptosis

肺动脉高压（pulmonary artery hypertension，PAH）是一组由多种病因累及肺血管床而引起肺动脉平滑肌细胞（PASMCs）增生和肺动脉结构重塑以及肺动脉压力升高为特征的一种临床综合征[1]。PAH一旦形成，临床上尚无行之有效的根治措施。因此，PAH有着“心血管领域的癌症”之称[2]。肺血管重塑在PAH发病中起关键性作用，且PASMCs异常增殖是构成肺动脉血管重塑的主要病理生理基础[3]。因此，探索介导PASMCs异常增殖的分子机制及相关药物干预是PAH领域的研究热点。

研究证实，阿托伐他汀钙（ATV）通过钙调通道差异性表达来减弱野百合碱诱导的PAH大鼠的肺动脉重构[4]。Guerard等[5]证明普伐他汀可抑制野百合碱诱导的PAH进展，改善肺动脉内皮依赖性舒张功能。此外，Taraseviciene-Stewart等[6]研究提示辛伐他汀能够显著降低平均肺动脉压力，缓解右室肥厚，其机制可能与抑制凋亡蛋白Caspase-3激活、减少肺微血管内皮细胞凋亡有关。信号转导通路磷酸肌醇3-激酶/蛋白激酶B（PI3K/AKT）是许多生命活动中关键的信号转导分子，参与调控细胞分裂﹑分化﹑凋亡、增殖及迁移等活动。……