阿托伐他汀通过调节脂肪酸代谢相关蛋白改善野百合碱诱导的肺高血压大鼠肺动脉平滑肌细胞增殖  

Atorvastatin attenuates pulmonary arterial smooth muscle cells proliferation by mediating fatty acid metabolism in monocrotaline-induced pulmonary arterial hypertension rats

作　　者：黄邦邦 陈嫒 龚瑾 练桂丽 罗莉[1] HUANG Bang-bang;CHEN Ai;Gong Jin;LIAN Gui-li;LUO Li(Dempartmant of Geriatrics,Fujian Hy pertemion Research Institute,The First Affiliated Hospital of Fujian Medical University,Fuzhou,Fujian 350005,China)

机构地区：[1]福建医科大学附属第一医院老年科,福建省高血压研究所,福建福州350005

出　　处：《中华高血压杂志》2021年第9期847-854,共8页Chinese Journal of Hypertension

基　　金：福建省卫生计生委科研课题(2018-1-55);国家自然科学基金(面上项目)(81770501);福建省自然科学基金面上项目(2018J01160)。

摘　　要：目的探索阿托伐他汀对野百合碱诱导的肺动脉高压(PAH)大鼠肺动脉平滑肌细胞(PASMC)增殖的影响及其可能的机制。方法将30只雄性成年SD大鼠随机分为3组:对照组、PAH组以及阿托伐他汀组(ATO组),其中15只用于动物实验,另外15只用于细胞实验。PAH组大鼠接受腹腔注射野百合碱建立大鼠PAH模型,ATO组大鼠除了腹腔注射野百合碱之外,通过灌胃接受阿托伐他汀治疗。在野百合碱造模后第4周周末,Western blot检测固醇调节元件结合蛋白1-c(SREBP1-c)、乙酰辅酶A羧化酶1(ACC1)、乙酰辅酶羧化酶2(ACC2)、磷酸化ACC1(P-ACC1)和磷酸化ACC2(P-ACC2)。另外,以肺组织和PASMC内增殖细胞核抗原(PCNA)的表达水平以及3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)染色法来评估PASMC增殖水平。结果野百合碱腹腔注射后第4周周末,PAH组的SREBP1-c、ACC1和ACC2在肺组织内以及PASMC内表达水平较对照组降低,而ATO组的水平较PAH组升高。野百合碱干预后,大鼠肺组织以及PASMC内的PCNA、P-ACC1和P-ACC2的表达水平明显增高,而阿托伐他汀可部分逆转这一过程。同时,MTT染色显示血小板源性生长因子(PDFG-BB)干预过后的PASMC的增殖水平较对照组明显增高,而阿托伐他汀可改善这一过程[对照组(0.15±0.01)比PDGF-BB组(0.27±0.04)比10^(-5)mol/L ATO组(0.17±0.02)比10^(-6)mol/L ATO组(0.20±0.04),P<0.05]。结论阿托伐他汀可以改善野百合碱诱导的PASMC增殖,而这一作用可能是由于其调节脂肪酸代谢相关SREBP1-c/ACC通路而产生。Objective To investigate the effects of atorvastatin on pulmonary arterial smooth muscle cells(PASMC)proliferation in pulmonary arterial hypertension(PAH)rats and the possible mechanisms.Methods Thirty male adult Sprague-Dawley rats were randomly divided into:control(Ctrl)group,PAH group and atorvastatin(ATO)group with 15 rats used in animal experiments and another 15 rats in cell experiments.Rats in PAH group were injected intraperitoneally with monocrotaline to establish PAH model,while rats in ATO group received atorvastatin through gavage in addition to monocrotaline injection.At the end of 4th week after monocrotaline injection,the expression levels of sterol regulatory element binding protein 1-c(SREBP1-c),acetyl-CoA carboxylase 1(ACC1),acetyl-CoA carboxylase 2(ACC2),phosphorylated ACC 1(P-ACC1)and phosphorylated ACC2(P-ACC2)in lung tissues and PASMC were determined by Western blot respectively.PASMC proliferation level was evaluated by protein level of proliferating cell nuclear antigen(PCNA)in lung tissues and PASMC,and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazol-3-ium bromide(MTT)staining.Results At the end of 4th week after monocrotaline injection,the protein levels of SREBP1-c,ACC1 and ACC2 in lungs and PASMC in PAH rats were much lower than those in Ctrl group but higher than those in ATO group.After intervention with monocrotaline,the expression of PCNA,P-ACC1 and P-ACC2 significantly increased in both lung tissues and PASMC,which was partly regressed by atorvastatin.Meanwhile,the MTT staining also showed a marked increase of PASMC proliferation after intervention of platelet-derived growth factor-BB(PDGF-BB)compared with Ctrl group,which was attenuated by atorvastatin(Ctrl group 0.15±0.01 vs PDGF-BB group 0.27±0.04 vs 10^(-5)mol/L ATO group 0.17±0.02 vs 10^(-6)mol/L ATO group 0.20±0.04,P<0.05).Conclusion Atorvastatin attenuates PASMC proliferation in monocrotaline-induced PAH rats probably by mediating SREBP1-c/ACC pathway related to fatty acid metabolism.

关 键 词：肺动脉平滑肌细胞 增殖 阿托伐他汀 脂肪酸代谢 

分 类 号：R544.1[医药卫生—心血管疾病]