热应激对大鼠胸主动脉内皮细胞生物钟基因 Bmal1和细胞周期蛋白表达水平的影响

doi:10.12122/j.issn.1673-4254.2025.07.01

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (7): 1353-1362.doi: 10.12122/j.issn.1673-4254.2025.07.01

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热应激对大鼠胸主动脉内皮细胞生物钟基因 Bmal1和细胞周期蛋白表达水平的影响

常笑语¹(), 张瀚文²(), 曹红亭², 侯玲², 孟鑫¹, 陶虹², 罗彦³(), 李光华¹^,²()

^1.宁夏医科大学，公共卫生学院，宁夏银川 750004
^2.宁夏医科大学，基础医学院，宁夏银川 750004
^3.肇庆医学院基础医学院，广东肇庆 526020

收稿日期:2024-06-21 接受日期:2025-04-25 出版日期:2025-07-20 发布日期:2025-07-17
通讯作者: 罗彦,李光华 E-mail:xiaoxyyu@163.com;1912118742@qq.com;wyzxsh@hotmail.com;ghlee0404@163.com
作者简介:常笑语，博士，E-mail： xiaoxyyu@163.com
张瀚文，硕士，E-mail： 1912118742@qq.com
第一联系人：常笑语、张瀚文共同为第一作者
基金资助:
宁夏自然科学基金(2023AAC03218);宁夏自然科学基金(2023AAC03237)

Heat stress affects expression levels of circadian clock gene Bmal1 and cyclins in rat thoracic aortic endothelial cells

Xiaoyu CHANG¹(), Hanwen ZHANG²(), Hongting CAO², Ling HOU², Xin MENG¹, Hong TAO², Yan LUO³(), Guanghua LI¹^,²()

^1.School of Public Health, Zhaoqing Medical College, Zhaoqing 526020, China
^2.School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China, Zhaoqing Medical College, Zhaoqing 526020, China
^3.School of Basic Medicine Sciences, Zhaoqing Medical College, Zhaoqing 526020, China

Received:2024-06-21 Accepted:2025-04-25 Online:2025-07-20 Published:2025-07-17
Contact: Yan LUO, Guanghua LI E-mail:xiaoxyyu@163.com;1912118742@qq.com;wyzxsh@hotmail.com;ghlee0404@163.com
About author:First author contact:CHANG Xiaoyu and ZHANG Hanwen contributed equally to this work
Supported by:
Natural Science Foundation of Ningxia Hui Autonomous Region(2023AAC03218)

摘要/Abstract

摘要：

目的研究热应激条件下大鼠胸主动脉结构的变化以及胸主动脉内皮细胞Bmal1和周期蛋白表达水平的变化。方法选取20只雄性SD大鼠，随机分为对照组和热应激组（各10只），用HE染色法观察胸主动脉的组织病理学变化，免疫组化法检测胸主动脉中Bmal1的表达。体外实验采用大鼠胸主动脉内皮细胞（RTAECs），分为对照组、阴性对照组、阴性热暴露组、热暴露组（HS）、Bmal1干扰（si-Bmal1）组和 si-Bmal1+HS 组。体内和体外实验均采用 Western blotting检测 Bmal1、细胞周期蛋白 CDK1、CDK4、CDK6 和 cyclin B1 以及凋亡相关蛋白 Bax和Bcl-2 的表达。TUNEL法检测胸主动脉中的细胞凋亡，流式细胞术检测RTAECs的细胞周期分布和凋亡水平变化。结果与对照组相比，热应激组大鼠血压升高，心率减慢，胸主动脉出现弹力纤维断裂，Bmal1、cyclin B1 和 CDK1 表达增加。体外结果显示，与对照组相比，热应激组 RTAECs 中 Bmal1、cyclin B1 和 CDK1 蛋白表达水平升高；si-Bmal1转染逆转了热应激引起的细胞周期蛋白表达改变并抑制热应激诱导的细胞凋亡，表现为 Bax 表达降低和 Bcl-2 表达升高（P<0.05）。结论热应激上调大鼠胸主动脉内皮细胞中生物钟基因Bmal1和细胞周期蛋白的表达，最终引发细胞凋亡。抑制Bmal1的表达可逆转热应激诱导的大鼠胸主动脉上皮细胞损伤，并在一定程度上缓解热应激引起的细胞周期变化。

关键词: 热应激, 生物钟基因, Bmal1, 胸主动脉内皮细胞, 周期蛋白, 细胞凋亡

Abstract:

Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress. Methods Twenty male SD rats were randomized equally into control group and heat stress group. After exposure to 32 ℃ for 2 weeks in the latter group, the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry. In the cell experiments, cultured rat thoracic aortic endothelial cells (RTAECs) were incubated at 40 ℃ for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA (si-Bmal1) or a negative sequence. In both rat thoracic aorta and RTAECs, the expressions of Bmal1, the cell cycle proteins CDK1, CDK4, CDK6, and cyclin B1, and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting. TUNEL staining was used to detect cell apoptosis in rat thoracic aorta, and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry. Results Compared with the control rats, the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1, cyclin B1 and CDK1 in the thoracic aorta (P<0.05). In cultured RTAECs, heat stress caused significant increase of Bmal1, cyclin B1 and CDK1 protein expression levels, which were obviously lowered in cells with prior si-Bmal1 transfection. Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2. Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells, which can be partly alleviated by suppressing Bmal1 expression.

Key words: heat stress, circadian clock genes, Bmal1, thoracic aortic endothelial cells, cyclins, apoptosis

常笑语, 张瀚文, 曹红亭, 侯玲, 孟鑫, 陶虹, 罗彦, 李光华. 热应激对大鼠胸主动脉内皮细胞生物钟基因 Bmal1和细胞周期蛋白表达水平的影响[J]. 南方医科大学学报, 2025, 45(7): 1353-1362.

Xiaoyu CHANG, Hanwen ZHANG, Hongting CAO, Ling HOU, Xin MENG, Hong TAO, Yan LUO, Guanghua LI. Heat stress affects expression levels of circadian clock gene Bmal1 and cyclins in rat thoracic aortic endothelial cells[J]. Journal of Southern Medical University, 2025, 45(7): 1353-1362.

图/表 7

Tab.1 Primer sequences and the expected product sizes

Gene	Sequence (5'-3')	Length (bp)
Bmal1		108
Forward	ACCCATACACAGAAGCAAACTACA
Reverse	GGTCACATCCTACGACAAACAAA
β-actin		140
Forward	CCTAGACTTCGAGCAAGAGA
Reverse	GGAAGGAAGGCTGGAAGA

Fig.1 Effect of heat stress on blood pressure, heart rate and structure of the thoracic aorta in rats. A: Blood pressure of the rats before and after heat stress. B: Heart rate of the rats before and after heat stress. C: HE staining of the thoracic aorta of the rats (Original magnification:×40). Data are presented as Mean±SD from 8 independent measurements. *P<0.05, **P<0.01 vs control (Con). SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HS: Heat stress.

Fig.2 Heat stress increases Bmal1 expression in rat thoracic aorta and rat thoracic aortic endothelial cells (RTAECs). A: Bmal1 mRNA expression levels of in rat thoracic aorta. B: Immunohistochemical detection of Bmal1 protein in rat thoracic aorta (×40). C, D: Western blotting and quantitative analysis of Bmal1 protein expression in RTAECs with heat stress at different temperatures. E, F: Western blotting and quantitative analysis of Bmal1 protein expression in RTAECs with heat stress of different lengths. Data are presented as Mean±SD from 3 independent experiments. *P<0.05, **P<0.01 vs Con.

Fig.3 Heat stress causes changes in cyclin expression and cell cycle progression in rat thoracic aorta and RTAECs. A, B: Western blotting for detecting the expressions of CDK4, CDK6, cyclin B1 and CDK1 proteins in rat thoracic aorta. C, D: Western blotting for detecting CDK4, CDK6, cyclin B1 and CDK1 proteins in RTAECs. Data are presented as Mean±SD from 3 independent experiments. *P<0.05, **P<0.01 vs Con.

Fig.4 Efficiency of the siRNA constructs for Bmal1 knockdown and effect of siRNA2 on mRNA and protein Bmal1 expressions in RTAECs. A: Bmal1 mRNA expression levels in RTAECs transfected with different si-Bmal1 constructs. B: Western blotting for detecting Bmal1 protein expressions in the transfected cells. C: Bmal1 mRNA expression levels in RTAECs with heat stress, transfection with si-Bmal1, or both. D: Western blotting for detecting Bmal1 protein expression in different treatment groups. Data are presented as Mean±SD from 3 independent experiments. *P<0.05, **P<0.01. NC: Negative control.

Fig.5 Bmal1 knockdown reverses heat stress-induced changes in cyclin expression and cell cycle in RTAECs. A, B: Cell cycle distribution in treated RTAECs. C-F: Western blotting for detecting CDK6, CDK1 and cyclin B1 protein expressions in the treated cells. Data are presented as Mean±SD from 3 independent experiments. *P<0.05, **P<0.01.

Fig.6 Bmal1 knockdown suppresses heat stress-induced apoptosis in RTAECs. A: TUNEL assay for assessing apoptosis in rat thoracic aorta. B, C: Western blotting for detecting Bax and Bcl-2 protein expressions in RTAECs. D, E: Flow cytometric analysis of apoptosis of RTAECs in different groups. Data are presented as Mean±SD from 3 independent experiments. *P<0.05, **P<0.01.

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热应激对大鼠胸主动脉内皮细胞生物钟基因 Bmal1和细胞周期蛋白表达水平的影响

Heat stress affects expression levels of circadian clock gene Bmal1 and cyclins in rat thoracic aortic endothelial cells

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