番泻苷A对2型糖尿病小鼠动脉粥样硬化斑块形成及5-羟色胺信号分子表达的影响

doi:10.3969/j.issn.1674-8115.2024.08.008

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (8): 991-998.doi: 10.3969/j.issn.1674-8115.2024.08.008

番泻苷A对2型糖尿病小鼠动脉粥样硬化斑块形成及5-羟色胺信号分子表达的影响

刘美志¹(), 王子杨¹, 姜雅宁¹, 弥萌², 孙永宁¹()

^1.上海中医药大学附属市中医医院心病科，上海 200071
^2.陕西中医药大学第一临床医学院，西安 712046

收稿日期:2024-02-08 接受日期:2024-04-15 出版日期:2024-08-28 发布日期:2024-08-27
通讯作者: 孙永宁 E-mail:Mary53194@126.com;ynsun2002@126.com
作者简介:刘美志（1994—），女，博士生；电子信箱：Mary53194@126.com。
基金资助:
国家自然科学基金(8207140172)

Effects of sennoside A on atherosclerotic plaque formation and expression of 5-hydroxytryptamine signal moleculars in mice with diabetes mellitus type 2

LIU Meizhi¹(), WANG Ziyang¹, JIANG Yaning¹, MI Meng², SUN Yongning¹()

^1.Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
^2.The First Clinical Medical College, Shaanxi University of Chinese Medicine, Xi'an 712046, China

Received:2024-02-08 Accepted:2024-04-15 Online:2024-08-28 Published:2024-08-27
Contact: SUN Yongning E-mail:Mary53194@126.com;ynsun2002@126.com
Supported by:
National Natural Science Foundation of China(8207140172)

摘要/Abstract

摘要：

目的·研究番泻苷A（sennoside A，SA）对2型糖尿病（diabetes mellitus type 2，T2DM）小鼠动脉粥样硬化斑块形成和5-羟色胺（5-hydroxytryptamine，5-HT）及其受体表达的影响。方法·将载脂蛋白E基因敲除小鼠12只随机分为模型组（model组）和治疗组（model+SA组），每组6只，同遗传背景C57BL/6J小鼠6只作为对照组（control组）。Control组普通饲养，model组和model+SA组在高脂饲养基础上每日给予腹腔注射30 mg/kg链脲佐菌素（streptozotocin，STZ）建立T2DM模型。Model+SA组每日给予SA（45 mg/kg）灌胃干预8周，control组和model组给予等体积双蒸水灌胃。比较造模及治疗前后小鼠体质量、空腹血糖和餐后2 h血糖情况，采用油红O染色和苏木精-伊红染色（hematoxylin-eosin staining，H-E染色）观察小鼠主动脉斑块面积，并用ELISA试剂盒测定小鼠血清和胸主动脉中5-HT水平，采用蛋白质印迹法（Western blotting）检测小鼠胸主动脉中5-羟色胺2B受体（5-hydroxytryptamine receptor 2B，HTR2B）和5-羟色胺转运蛋白（serotonin transporter，SERT）的表达情况。结果·与control组相比，model组小鼠体质量、空腹血糖和餐后2 h血糖均升高，糖代谢紊乱；主动脉斑块形成，胸主动脉中HTR2B、SERT蛋白表达升高；胸主动脉5-HT浓度降低，血清5-HT浓度升高（均P<0.05）。给予SA治疗后，与model组相比，model+SA组小鼠体质量下降，空腹血糖和餐后2 h血糖水平明显改善；主动脉斑块面积减少，胸主动脉HTR2B、SERT蛋白表达显著降低；胸主动脉5-HT浓度升高，血清5-HT浓度降低（均P<0.05）。结论·SA可减少T2DM小鼠动脉粥样硬化斑块面积，其作用可能与降低血糖、抑制5-HT及其受体表达有关。

关键词: 番泻苷A, 2型糖尿病, 动脉粥样硬化, 5-羟色胺, 5-羟色胺2B受体

Abstract:

Objective ·To investigate the effects of sennoside A (SA) on the formation of atherosclerotic plaque and the expression of 5-hydroxytryptamine (5-HT) and its receptor in mice with diabetes mellitus type 2 (T2DM). Methods ·Twelve mice with knocked-out apolipoprotein E gene were randomly divided into two groups, namely the model group and the model+SA group, with six mice in each group. Six C57BL/6J mice with the same genetic background were used as the control group. The control group was fed with normal diet, and the model group and the model+SA group were given intraperitoneal injection of streptozotocin (30 mg/kg) daily on the basis of high-fat diet to establish a model of T2DM. The model+SA group was given SA daily by gavage for 8 weeks, and the control group and the model group were given equal volume of distillation-distillation H₂O by gavage. The body weight, fasting blood glucose (FBG) and 2-h postprandial blood glucose of mice were compared before and after modeling and treatment. The area of aortic plaque was observed by oil red O staining and hematoxylin-eosin (H-E) staining, and the level of 5-HT in serum and thoracic aorta was measured by ELISA kit. Western blotting was used to detect the expression of 5-hydroxytryptamine receptor 2B (HTR2B) and serotonin transporter (SERT) in thoracic aorta of mice. Results ·Compared with the control group, the body weight, FBG and 2-h postprandial blood glucose in the model group increased, and glucose metabolism was disordered. The expression of HTR2B and SERT protein in thoracic aorta increased, while the concentration of 5-HT in thoracic aorta decreased. The serum 5-HT concentration increased (all P<0.05). After treatment with SA, compared with the model group, the body weight of the model+SA group decreased, and FBG and 2-h postprandial blood glucose were significantly improved. The area of aortic plaque and the expression of HTR2B and SERT protein in thoracic aorta significantly decreased, while the concentration of 5-HT increased. The serum 5-HT concentration decreased (all P<0.05). Conclusion ·SA can reduce atherosclerotic plaque area in T2DM mice, which may be related to lowering blood glucose and inhibiting the expression of 5-HT and its receptor.

Key words: sennoside A (SA), diabetes mellitus type 2 (T2DM), atherosclerosis, 5-hydroxytryptamine (5-HT), 5-hydroxytryptamine receptor 2B (HTR2B)

中图分类号:

R587.1

刘美志, 王子杨, 姜雅宁, 弥萌, 孙永宁. 番泻苷A对2型糖尿病小鼠动脉粥样硬化斑块形成及5-羟色胺信号分子表达的影响[J]. 上海交通大学学报（医学版）, 2024, 44(8): 991-998.

LIU Meizhi, WANG Ziyang, JIANG Yaning, MI Meng, SUN Yongning. Effects of sennoside A on atherosclerotic plaque formation and expression of 5-hydroxytryptamine signal moleculars in mice with diabetes mellitus type 2[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(8): 991-998.

图/表 7

图1 治疗后各组小鼠一般状态

Fig 1 General state of mice in each group after treatment

表1 治疗前后小鼠体质量比较

Tab 1 Comparison of body weight of mice before and after treatment

Item

Body weight/g

Control group (n=6)

Model group

(n=6)

表2 治疗前后小鼠血糖比较

Tab 2 Comparison of blood glucose in mice before and after treatment

Item	Control group (n=6)	Model group (n=6)	Model+SA group (n=6)
Before treatment
FBG/(mmol·L^-1)	4.85±0.55	16.87±3.89^①	18.95±4.59
PBG/(mmol·L^-1)	6.67±0.77	21.53±2.96^①	21.07±2.67
After treatment
FBG/(mmol·L^-1)	4.88±1.11	21.97±5.33^①	16.12±2.05^②
PBG/(mmol·L^-1)	7.07±0.64	25.03±4.29^①	19.60±2.70^③

表3 治疗前后小鼠5-HT浓度比较

Tab 3 Comparison of 5-HT concentration in mice before and after treatment

Item

5-HT concentration/(ng·mL^-1)

Control group

(n=6)

Model group

(n=6)

图2 各组小鼠主动脉斑块面积比较Note： A. Representative images of aortic plaque. B. Portion of aortic plaque area. ①P=0.000, compared with the control group; ②P=0.013, compared with the model group.

Fig 2 Comparison of aortic plaque area in mice in each group

图3 各组小鼠胸主动脉病理形态

Fig 3 Pathological morphology of thoracic aorta of mice in each group

图4 各组小鼠SERT、HTR2B蛋白表达量比较Note： A. Representative Western blotting bands. B. Quantification of Western blotting bands. ①P=0.007, ③P=0.005, compared with the control group; ②P=0.009, ④P=0.027, compared with the model group.

Fig 4 Comparison of SERT and HTR2B protein expression levels in mice in each group

参考文献 35

1	Chinese Diabetes Society. 中国2型糖尿病防治指南 (2020年版) (上)[J]. 中国实用内科杂志, 2021, 41(8): 668-695.
	Chinese Diabetes Society. Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition) (Part 1)[J]. Chinese Journal of Practical Internal Medicine, 2021, 41(8): 668-695.
2	MOSENZON O, ALGUWAIHES A, LEON J L A, et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries[J]. Cardiovasc Diabetol, 2021, 20(1): 154.
3	WONG N D, SATTAR N. Cardiovascular risk in diabetes mellitus: epidemiology, assessment and prevention[J]. Nat Rev Cardiol, 2023, 20(10): 685-695.
4	YAO C Y, WANG Z Y, JIANG H Y, et al. Ganoderma lucidum promotes sleep through a gut microbiota-dependent and serotonin-involved pathway in mice[J]. Sci Rep, 2021, 11(1): 13660.
5	YOUNG R L, LUMSDEN A L, MARTIN A M, et al. Augmented capacity for peripheral serotonin release in human obesity[J]. Int J Obes, 2018, 42(11): 1880-1889.
6	IMAMDIN A, VAN DER VORST E P C. Exploring the role of serotonin as an immune modulatory component in cardiovascular diseases[J]. Int J Mol Sci, 2023, 24(2): 1549.
7	金霄, 吴敏. 动脉粥样硬化从“伏毒”论治[J]. 辽宁中医杂志, 2024, 51(6): 39-42.
	JIN X, WU M. Treatment of atherosclerosis from "Fudu"[J]. Liaoning Journal of Traditional Chinese Medicine, 2024, 51(6): 39-42.
8	谭明义, 陈根成, 唐纯志. 大黄胶囊预防脑梗塞并发应激性胃溃疡的实验研究[J]. 广州中医药大学学报, 2001, 18(2): 149-151.
	TAN M Y, CHEN G C, TANG C Z. Preventive effects of Radix et Rhizoma Rhei Granule on the occurrence of complicated stress ulcer of stomach in rats after cerebral infarction[J]. Journal of Guangzhou University of Traditional Chinese Medicine, 2001, 18(2): 149-151.
9	宋少伟, 路瑷雯, 董燕平, 等. 大黄䗪虫丸防治动脉粥样硬化的作用机制及临床研究进展[J]. 现代中西医结合杂志, 2022, 31(24): 3495-3499.
	SONG S W, LU A W, DONG Y P, et al. The mechanism and clinical research progress of Dahuang Zhechong pills in the prevention and treatment of atherosclerosis[J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2022, 31(24): 3495-3499.
10	MA L, CAO X Y, YE X T, et al. Sennoside A induces GLP-1 secretion through activation of the ERK1/2 pathway in L-cells[J]. Diabetes Metab Syndr Obes, 2020, 13: 1407-1415.
11	朱红. 番泻苷A通过抑制DNMT1介导的PTEN高甲基化改善四氯化碳诱导的小鼠肝纤维化[D]. 合肥: 安徽医科大学, 2021.
	ZHU H. Protective effects and mechanisms of sennoside A on CCl₄-induced hepatic fibrosis in mice[D]. Hefei: Anhui Medical University, 2021.
12	LE J M, FU Y, HAN Q Q, et al. Transcriptome analysis of the inhibitory effect of sennoside A on the metastasis of hepatocellular carcinoma cells[J]. Front Pharmacol, 2020, 11: 566099.
13	周吉, 王海燕, 王子晨, 等. 基于“脉络学说”和“瘀血理论”探讨糖尿病大血管病变氧化应激机制[J]. 河北中医, 2024, 46(3): 485-488, 492.
	ZHOU J, WANG H Y, WANG Z C, et al. To explore the mechanism of oxidative stress in diabetic macroangiopathy based on "vein theory" and "blood stasis theory"[J]. Hebei Journal of Traditional Chinese Medicine, 2024, 46(3): 485-488, 492.
14	姚建莉, 梁永林, 任梦函, 等. 大黄糖络丸通过调控PI3K-Akt/NF-κB信号通路减轻糖尿病大鼠大血管炎症反应[J]. 中国病理生理杂志, 2024, 40(4): 646-652.
	YAO J L, LIANG Y L, REN M H, et al. Rhubarb sugar pills attenuate inflammatory response in large blood vessels of diabetic rats by regulating PI3K-Akt/NF-κB signaling pathway[J]. Chinese Journal of Pathophysiology, 2024, 40(4): 646-652.
15	HUANG H H, LIAO D, DONG Y, et al. Effect of quercetin supplementation on plasma lipid profiles, blood pressure, and glucose levels: a systematic review and meta-analysis[J]. Nutr Rev, 2020, 78(8): 615-626.
16	刘亚洲, 姜静雨, 拉毛才旦, 等. 大黄的降血脂生物活性成分及作用机制研究进展[J]. 食品安全质量检测学报, 2023, 14(11): 272-282.
	LIU Y Z, JIANG J Y, LAMAO C D, et al. Research progress on the hypolipidemic bioactive components andmechanism of action of Rheum[J]. Journal of Food Safety & Quality, 2023, 14(11): 272-282.
17	王静, 李玉婷, 刘大伟, 等. 大黄蒽醌类主要有效成分抗肾纤维化作用机制的研究进展[J]. 中医研究, 2023, 36(10): 92-96.
	WANG J, LI Y T, LIU D W, et al. Research progress on the anti-renal fibrosis mechanism of the main active components of anthraquinones in Radix et Rhizoma Rhei[J]. Traditional Chinese Medicinal Research, 2023, 36(10): 92-96.
18	WEI Z H, SHEN P L, CHENG P, et al. Gut bacteria selectively altered by sennoside A alleviate type 2 diabetes and obesity traits[J]. Oxid Med Cell Longev, 2020, 2020: 2375676.
19	LE J M, ZHANG X Y, JIA W P, et al. Regulation of microbiota-GLP1 axis by sennoside A in diet-induced obese mice[J]. Acta Pharm Sin B, 2019, 9(4): 758-768.
20	GOJANI E G, WANG B, LI D P, et al. The impact of psilocybin on high glucose/lipid-induced changes in INS-1 cell viability and dedifferentiation[J]. Genes, 2024, 15(2): 183.
21	ASUAJE PFEIFER M, LIEBMANN M, BEUERLE T, et al. Role of serotonin (5-HT) in GDM prediction considering islet and liver interplay in prediabetic mice during gestation[J]. Int J Mol Sci, 2022, 23(12): 6434.
22	GEORGESCU T, LYONS D, HEISLER L K. Role of serotonin in body weight, insulin secretion and glycaemic control[J]. J Neuroendocrinol, 2021, 33(4): e12960.
23	SANTOS A P, COUTO C F, PEREIRA S S, et al. Is serotonin the missing link between COVID-19 course of severity in patients with diabetes and obesity?[J]. Neuroendocrinology, 2022, 112(11): 1039-1045.
24	CHOI W G, CHOI W, OH T J, et al. Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance[J]. J Clin Invest, 2021, 131(23): e145331.
25	WU B Y, YE Y, XIE S S, et al. Megakaryocytes mediate hyperglycemia-induced tumor metastasis[J]. Cancer Res, 2021, 81(21): 5506-5522.
26	LI L, ZHOU J W, WANG S, et al. Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia[J]. Haematologica, 2022, 107(6): 1358-1373.
27	朱奕霖, 彭婕, 施小凤. 整合素αⅡbβ3在血小板中作用的研究现状[J]. 国际输血及血液学杂志, 2023, 46(1): 26-33.
	ZHU Y L, PENG J, SHI X F. Research status on role of integrinαⅡbβ3 in platelets[J]. International Journal of Blood Transfusion and Hematology, 2023, 46(1): 26-33.
28	RIEDER M, GAUCHEL N, BODE C, et al. Serotonin: a platelet hormone modulating cardiovascular disease[J]. J Thromb Thrombolysis, 2021, 52(1): 42-47.
29	ZHU J S, YANG L, JIA Y F, et al. Pathogenic mechanisms of pulmonary arterial hypertension: homeostasis imbalance of endothelium-derived relaxing and contracting factors[J]. JACC Asia, 2022, 2(7): 787-802.
30	BUGA A M, CIOBANU O, BĂDESCU G M, et al. Up-regulation of serotonin receptor 2B mRNA and protein in the peri-infarcted area of aged rats and stroke patients[J]. Oncotarget, 2016, 7(14): 17415-17430.
31	WENGLÉN C, DEMIREL I, EREMO A G, et al. Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells[J]. Eur J Pharmacol, 2023, 944: 175570.
32	FONG F, XIAN J, DEMER L L, et al. Serotonin receptor type 2B activation augments TNF-α-induced matrix mineralization in murine valvular interstitial cells[J]. J Cell Biochem, 2021, 122(2): 249-258.
33	闻松, 杨长坤, 江平. 5-羟色胺及其受体拮抗剂在心血管疾病中的研究现状[J]. 河北医科大学学报, 2021, 42(12): 1475-1481.
	WEN S, YANG C K, JIANG P. Research status of serotonin and its receptor antagonists in cardiovascular diseases[J]. Journal of Hebei Medical University, 2021, 42(12): 1475-1481.
34	ZHANG Y, CHEN Y B, CHEN G, et al. Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT[J]. Cell Mol Biol Lett, 2020, 25: 45.
35	MAULER M, HERR N, SCHOENICHEN C, et al. Platelet serotonin aggravates myocardial ischemia/reperfusion injury via neutrophil degranulation[J]. Circulation, 2019, 139(7): 918-931.

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番泻苷A对2型糖尿病小鼠动脉粥样硬化斑块形成及5-羟色胺信号分子表达的影响

Effects of sennoside A on atherosclerotic plaque formation and expression of 5-hydroxytryptamine signal moleculars in mice with diabetes mellitus type 2

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