激活ALDH2通过上调SIRT1/PGC-1α信号通路减轻小鼠缺氧性肺动脉高压

doi:10.12122/j.issn.1673-4254.2024.10.14

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (10): 1955-1964.doi: 10.12122/j.issn.1673-4254.2024.10.14

• • 上一篇

激活ALDH2通过上调SIRT1/PGC-1α信号通路减轻小鼠缺氧性肺动脉高压

王磊¹^,²(), 卞芬兰¹^,², 马飞扬³, 方舒³, 凌梓涵³, 刘梦然³, 孙红燕¹^,², 付程文⁴, 倪诗垚⁵, 赵晓阳¹, 冯心茹¹, 孙正宇¹^,², 卢国庆¹^,², 康品方¹^,²(), 吴士礼¹^,²()

^1.蚌埠医科大学第一附属医院心血管科，安徽蚌埠 233000
^2.蚌埠医科大学心脑血管基础与临床重点实验室，安徽蚌埠 233000
^3.蚌埠医科大学临床医学院，安徽蚌埠 233000
^4.蚌埠医科大学第一附属医院麻醉科，安徽蚌埠 233000
^5.蚌埠医科大学第一附属医院耳鼻喉科，安徽蚌埠 233000

收稿日期:2024-05-31 出版日期:2024-10-20 发布日期:2024-10-31
通讯作者: 康品方,吴士礼 E-mail:568733358@qq.com;kangpinfang.1016@163.com;chinawsl@126.com
作者简介:王磊，在读硕士研究生，E-mail: 568733358@qq.com
基金资助:
国家自然科学基金(81970313);安徽省自然科学基金(2208085MH192);安徽省高校协同创新项目(GXXT-2020-019);安徽省优秀青年基金(2022AH030141);安徽省优秀创新团队(2022AH 010083);蚌埠医学院研究生科研创新计划项目(Byycx23099);安徽省临床转化课题青年项目(202304295107020034)

Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway

Lei WANG¹^,²(), Fenlan BIAN¹^,², Feiyang MA³, Shu FANG³, Zihan LING³, Mengran LIU³, Hongyan SUN¹^,², Chengwen FU⁴, Shiyao NI⁵, Xiaoyang ZHAO¹, Xinru FENG¹, Zhengyu SUN¹^,², Guoqing LU¹^,², Pinfang KANG¹^,²(), Shili WU¹^,²()

^1.Department of Cardiology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^2.Key Laboratory of Cardio-Cerebrovascular Foundation and Clinical Sciences, Bengbu Medical University, Bengbu 233000, China
^3.Clinical College of Medicine, Bengbu Medical University, Bengbu 233000, China
^4.Department of Anesthesiology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
^5.Department of Otolaryngology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China

Received:2024-05-31 Online:2024-10-20 Published:2024-10-31
Contact: Pinfang KANG, Shili WU E-mail:568733358@qq.com;kangpinfang.1016@163.com;chinawsl@126.com
Supported by:
National Natural Science Foundation of China(81970313)

摘要/Abstract

摘要：

目的探讨激活线粒体乙醛脱氢酶2（ALDH2）是否可以通过SIRT1/PGC-1α信号通路减轻缺氧性肺动脉高压。方法在体水平：选取8周龄C57 BL/6小鼠40只，随机分成Control组、Hypoxia组、Hypoxia +Alda-1灌胃组及ALDH2特异性敲除组（Hypoxia +ALDH2^-/-），10只/组，Hypoxia组小鼠暴露于缺氧条件下（10%O₂，90%N₂），维持每日12 h/12 h的暗/光循环4周，Hypoxia+Alda-1组同时予以Alda-1腹腔注射处理４周，Control组予以常氧环境并给与同等量的溶剂（DMSO+PBS）干预４周。利用超声心动图、右心室导管实验评估右心功能及压力，以右心室压代替肺动脉压；HE评估肺血管重构及右心室损伤情况，免疫荧光检测α-SMA表达，评估肺远端小动脉肌化情况，WGA染色检测右心室横截面积，评估心肌细胞肥大程度，测量右心肥厚指数。检测ALDH2、SIRT1、PGC-1α、P16^INK4A、P21^CIP1蛋白表达。体外水平：分别设置Control组、Hypoxia组上、Hypoxia+Alda-1组上、Hypoxia+Alda-1+EX527组。利用β半乳糖染色评估各分组小鼠肺动脉平滑肌细胞衰老情况，Western blotting评估各分组蛋白表达情况。结果与Control组相比，Hypoxia组右心室收缩压（RVSP）增高、右室游离壁厚度（RVFWT）增厚、P16^INK4A、P21^CIP1表达增加（P<0.05）。与Hypoxia组相比，Hypoxia+Alda-1组RVSP降低、RVFWT变薄、P16^INK4A、P21^CIP1表达降低（P<0.05）。与Hypoxia组相比，Hypoxia+ALDH2^-/-组RVSP增高、RVFWT增厚、P16^INK4A、P21^CIP1蛋白表达增加（P<0.01）。与Control组相比，Hypoxia组细胞衰老比例增加、P16^INK4A、P21^CIP1表达增加（P<0.01）。与Hypoxia组相比，Hypoxia+Alda-1组细胞衰老比例降低（P<0.01），P16^INK4A、P21^CIP1（P<0.05）表达降低。与Hypoxia+Alda-1组相比，Hypoxia+Alda-1+EX527组细胞衰老比例增加（P<0.01），P16^INK4A、P21^CIP1表达增高（P<0.05）。结论 ALDH2通过调控SIRT1/PGC-1α信号通路，减轻小鼠肺动脉平滑肌细胞衰老，从而减轻缺氧型肺动脉高压。

关键词: 线粒体乙醛脱氢酶2, SIRT1, PGC-1α, 平滑肌细胞衰老, 肺动脉高压

Abstract:

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway. Methods Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2^-/-) mice, were exposed to hypoxia (10% O₂, 90% N₂) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α-SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21^CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting. Results The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16^INK4A and P21^CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2^-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16^INK4A and P21^CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment. Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Key words: ALDH2, SIRT1, PGC-1α, smooth muscle cell senescence, pulmonary hypertension

王磊, 卞芬兰, 马飞扬, 方舒, 凌梓涵, 刘梦然, 孙红燕, 付程文, 倪诗垚, 赵晓阳, 冯心茹, 孙正宇, 卢国庆, 康品方, 吴士礼. 激活ALDH2通过上调SIRT1/PGC-1α信号通路减轻小鼠缺氧性肺动脉高压[J]. 南方医科大学学报, 2024, 44(10): 1955-1964.

Lei WANG, Fenlan BIAN, Feiyang MA, Shu FANG, Zihan LING, Mengran LIU, Hongyan SUN, Chengwen FU, Shiyao NI, Xiaoyang ZHAO, Xinru FENG, Zhengyu SUN, Guoqing LU, Pinfang KANG, Shili WU. Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway[J]. Journal of Southern Medical University, 2024, 44(10): 1955-1964.

图/表 6

图1 功能学水平观察各组小鼠右心室压力、心功能指标变化

Fig.1 Comparison of right ventricular pressure (RVSP) and cardiac function of the mice among the groups. A: RVSP of the mice in each group. B: Heart color ultrasound in each group. C: Statistical diagram of RVSP in each group. D: Statistical diagram of maximum rise rate of RVSP in each group. E: Statistical map of right ventricular free wall thickness in each group. F: Statistical chart of pulmonary artery acceleration to ejection time ratio in each group. Data are presented as Mean±SD (n=6). *P<0.05, **P<0.01 vs control group; #P<0.05, ##P<0.01 vs hypoxia group.

图2 从组织学水平观察各组小鼠肺动脉重构情况

Fig.2 Pulmonary artery remodeling in each group. A: HE staining of pulmonary arteries in each group (scale bar=10 μm). B: Pulmonary artery smooth muscle to total vascular area ratio in each group. C: Percentage of pulmonary artery wall thickness to vessel diameter in each group. D: Immunofluorescence staining of pulmonary artery smooth muscle in each group (scale bar=6 μm). E: Relative fluorescence intensity of α-SMA in each group. Data are presented as Mean±SD (n=6). **P<0.01 vs control group; #P<0.05, ##P<0.01 vs hypoxia group.

图3 从组织学水平观察各组小鼠右心室重构情况

Fig.3 Right ventricular remodeling in each group. A: HE staining of the right ventricle in each group. B: Right ventricular cardiac hypertrophy index of each group. C: WGA staining of the right ventricle in each group. D: Cross-sectional area of mouse cardiomyocytes in each group. Data are presented as Mean±SD (n=6). **P<0.01 vs control group; #P<0.05, ##P<0.01 vs hypoxia group.

图4 从分子学水平观察各组小鼠肺组织ALDH2、SIRT1、PGC-1α、P16INK4A、P21CIP1蛋白表达情况

Fig.4 Wetsern blotting for detecting protein expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21CIP1 in the lung tissues in each group. A, B: Western blots of ALDH2 protein and its relative expression levels. C-E: Western blots of SIRT1 and PGC-1α proteins and their relative expression levels. F-H: Western blots of P16INK4A and P21CIP1 and their relative protein expression levels. Data are presented as Mean±SD (n=6). **P<0.01 vs control group; #P<0.05, ##P<0.01 vs hypoxia group.

图5 体外层面验证ALDH2通过SIRT1通路对细胞衰老的保护作用

Fig.5 Protective effect of ALDH2 against pulmonary artery smooth muscle cell senescence mediated by the SIRT1 pathway. A: Immunofluorescence staining for α-SMA for identification of mouse pulmonary artery smooth muscle cells. B: β-galactose staining of pulmonary artery smooth muscle cells in each group. C: Percentage of senescent cells in each group. Data are presented as Mean±SD (n=3). **P<0.01 vs control group; ##P<0.01 vs hypoxia group; &&P<0.01 vs Hypoxia+Alda-1 group.

图6 从体外水平观察各组小鼠ALDH2、SIRT1、PGC-1α、P16INK4A、P21CIP1蛋白表达情况

Fig.6 Protein expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21CIP1 in mouse pulmonary artery smooth muscle cells in each group. A, B: Western blots of ALDH2 protien and its relative expression levels. C-E: Western blots of SIRT1 and PGC-1α proteins and their relative expression levels. F-H: Western blots of P16INK4A and P21CIP1 proteins and their relative expression levels. Data are presented as Mean±SD (n=3). *P<0.05, **P<0.01 vs control group; #P<0.05, ##P<0.01 vs Hypoxia group; &&P<0.01 vs Hypoxia+Alda-1 group.

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激活ALDH2通过上调SIRT1/PGC-1α信号通路减轻小鼠缺氧性肺动脉高压

Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway

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