| 引用本文: |
张超, 易健, 丁蓉珍, 万佳婧, 谭骏岚, 王飞英, 周灵灵, 宋岚, 戴爱国.肺心汤通过调控AMPK/mTOR信号通路抑制自噬对低氧性肺动脉高压大鼠的保护作用[J].湖南中医药大学学报,2024,44(5):744-753[点击复制] |
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| 肺心汤通过调控AMPK/mTOR信号通路抑制自噬对低氧性肺动脉高压大鼠的保护作用 |
| 张超,易健,丁蓉珍,万佳婧,谭骏岚,王飞英,周灵灵,宋岚,戴爱国 |
| (湖南中医药大学医学院呼吸疾病研究室, 湖南 长沙 410208;血管生物学与转化医学湖南省重点实验室/湖南省 高校重点实验室, 湖南 长沙 410208;湖南中医药大学第一附属医院医学创新实验中心, 湖南 长沙 410007;湖南中医药大学第一附属医院呼吸内科, 湖南 长沙 410007;湖南中医药大学医学院, 湖南 长沙 410208) |
| 摘要: |
| 目的 探究肺心汤通过调控腺苷酸活化蛋白激酶（adenosine monophosphate-activated protein kinase，AMPK）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路对低氧性肺动脉高压（hypoxic pulmonary hypertension，HPH）大鼠的治疗作用及机制。方法 36只SD雄性大鼠随机分为正常组、模型组、西地那非组以及肺心汤低、中、高剂量组。除正常组外，将其余5组置于氧气浓度为10.0%±0.5%的低氧舱内造模28 d，每天8 h，造模同时灌胃给药。4周后检测大鼠心肺血流动力学指标[右心室收缩压（right ventricular systolic pressure，RVSP），右心室肥厚指数（right ventricular hypertrophy index，RVHI），肺动脉加速时间/肺动脉射血时间（pulmonary acceleration time/pulmonary ejection time，PAT/PET）、三尖瓣环收缩期位移（tricuspid annulus plane systolic excursion，TAPSE）、右心室前壁厚度（right ventricular anterior wall thickness，RVAWT）]；HE染色法检测肺动脉重塑；免疫荧光法检测α平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）和增殖细胞核抗原（proliferating cell nuclear antigen，PCNA）蛋白共定位表达；透射电镜观察自噬溶酶体的数量；免疫组织化学法检测肺组织中p-AMPK、p-mTOR、微管相关蛋白1轻链3B（microtubule-associated protein light chain 3B，LC3B）、Beclin1和p62蛋白阳性表达。结果 与正常组相比，模型组大鼠RVSP、RVHI及RVAWT显著升高（P<0.01），PAT/PET和TAPSE显著降低（P＜0.01）；肺小动脉壁明显增厚，管腔狭窄，肺小动脉管壁厚度占血管直径的百分比（the percentage of wall thickness of pulmonary arterioles to vascular diameter, WT%）显著升高（P＜0.01）；α-SMA和PCNA共定位表达显著增加；自噬溶酶体数量增加；肺组织中p-AMPK、LC3B和Beclin1蛋白阳性表达上调（P＜0.01），p-mTOR及p62蛋白阳性表达下调（P＜0.01）。与模型组相比，各给药组大鼠RVSP、RVHI及RVAWT 显著下降（P＜0.01），PAT/PET、TAPSE显著升高（P＜0.05，P＜0.01）；肺小动脉壁增厚程度减轻，WT%显著降低（P＜0.01）；α-SMA和PCNA共定位表达减少；自噬溶酶体数量减少；肺组织中p-AMPK、LC3B和Beclin1蛋白阳性表达显著下降（P＜0.05，P＜0.01），p-mTOR及p62蛋白阳性表达显著上调（P＜0.01）。与西地那非组相比，肺心汤低、中剂量组TAPSE降低（P＜0.01）；肺心汤低、中剂量组肺动脉中膜增厚程度增加，WT%增加（P＜0.01）；肺心汤低、中剂量组p-AMPK蛋白阳性表达升高（P＜0.01），肺心汤高剂量组p-AMPK蛋白阳性表达降低（P＜0.05）；肺心汤低剂量组p-mTOR蛋白阳性表达降低（P＜0.01）。结论 肺心汤可能通过下调AMPK/mTOR信号通路抑制自噬，发挥改善HPH的作用。 |
| 关键词: 肺心汤 低氧性肺动脉高压 腺苷酸活化蛋白激酶 哺乳动物雷帕霉素靶蛋白 自噬 |
| DOI：10.3969/j.issn.1674－070X.2024.05.005 |
| 投稿时间：2023-12-21 |
| 基金项目:国家自然科学基金面上项目（82370069，82200066）；国家自然科学基金青年项目（82305214）；湖南省自然科学基金项目（2021JJ30017，2022JJ40308）；中国博士后科学基金面上项目（2021M690982）；湖南省中医药科研计划重点项目（C2022001）；湖南省研究生科研创新项目（2022CX196）。 |
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| Protective effects of Feixin Decoction on rats with hypoxic pulmonary hypertension by inhibiting autophagy through regulating AMPK/mTOR signaling pathway |
| ZHANG Chao, YI Jian, DING Rongzhen, WAN Jiajing, TAN Junlan, WANG Feiying, ZHOU Lingling, SONG Lan, DAI Aiguo |
| (Respiratory Disease Laboratory, School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;Key Laboratory of Vascular Biology and Translational Medicine, Education Department of Hunan Province, Changsha, Hunan 410208, China;Medical Innovation Experiment Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410021, China;Department of Respiratory Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410021, China;School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To investigate the therapeutic efficacy and mechanism of Feixin Decoction (FXD) on hypoxic pulmonary hypertension (HPH) rats through regulating adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Methods Thirty-six SD rats were randomized into control group, model group, sildenafil group and low-, medium-, high-dose FXD groups. Except control group, the remaining five groups were placed in a hypoxic chamber with an oxygen concentration of 10%±0.5% for modeling, 8 hours per day for 28 d, with simultaneous intragastric administration. After 4 weeks, the rat cardiopulmonary hemodynamic indexes [right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), the ratio of pulmonary acceleration time to pulmonary ejection time (PAT/PET), tricuspid annulus plane systolic excursion (TAPSE), right ventricular anterior wall thickness (RVAWT)] were determined. Pulmonary artery remodeling was checked by HE staining; the co-localization of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) was examined by immunofluorescence assay; the number of autolysosomes was observed by transmission electron microscope (TEM); the positive expressions of p-AMPK, p-mTOR, microtubule-associated protein 1 light chain 3B (LC3B), Beclin1, and p62 in the lung tissue were measured by immunohistochemical assay. Results Compared with the control group, in the model group, RVSP, RVHI, and RVAWT were significantly increased (P<0.01), while PAT/PET and TAPSE were significantly decreased (P<0.01); the wall of the pulmonary arterioles was markedly thickened and the lumina narrowed, with a significant increase in the percentage of wall thickness of pulmonary arterioles to vascular diameter, WT% (P<0.01); the co-localization of α-SMA and PCNA was significantly enhanced (P<0.01); the number of autolysosomes was increased; the protein positive expressions of p-AMPK, LC3B, and Beclin1 in the lung tissue were up-regulated (P<0.01), while those of p-mTOR and p62 were down-regulated (P<0.01). Compared with the model group, in all medication groups, RVSP, RVHI, and RVAWT were significantly decreased (P<0.01), while PAT/PET and TAPSE were significantly increased (P<0.05, P<0.01); the thickness of the pulmonary arterioles was reduced with a significant reduction in WT% (P<0.01); the co-localization of α-SMA and PCNA was significantly reduced; the number of autolysosomes decreased; the protein positive expressions of p-AMPK, LC3B, and Beclin1 in the lung tissue were significantly down-regulated (P<0.05, P<0.01), while those of p-mTOR and p62 were significantly up-regulated (P<0.01). Compared with the sildenafil group, TAPSE decreased in the low- and medium-dose FXD groups (P<0.01); the degree of pulmonary arterial intima-media thickening was increased and the WT% was higher in the low- and medium-dose FXD groups (P<0.01); the protein positive expression of p-AMPK was elevated in the low- and medium-dose FXD groups (P<0.01), while that was reduced in the high-dose FXD group (P<0.05); the protein positive expression of p-mTOR was decreased in the low-dose FXD group (P<0.01). Conclusion FXD may play a role in ameliorating hypoxic pulmonary hypertension by inhibiting autophagy through down-regulation of the AMPK/mTOR signaling pathway. |
| Key words: Feixin Decoction hypoxic pulmonary hypertension adenosine monophosphate-activated protein kinase mammalian target of rapamycin autophagy |
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