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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 896-906. doi: 10.19723/j.issn.1671-167X.2022.05.017

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柚皮素抑制马凡综合征小鼠胸主动脉瘤的形成

李芷晴1,俞冰1,蔡泽宇1,王迎宝1,张煦1,周彪2,方晓红3,于芳1,付毅1,孙金鹏1,李伟4,孔炜1,*()   

  1. 1. 北京大学基础医学院生理学与病理生理学系，北京 100191
    2. 中日友好医院普外科，北京 100029
    3. 中国科学院化学研究所，北京 100190
    4. 北京大学人民医院血管外科，北京 100044
  • 收稿日期:2022-06-03 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 孔炜 E-mail:kongw@bjmu.edu.cn
  • 作者简介:孔炜，教授，博士生导师，北京大学基础医学院生理学与病理生理学系主任。教育部长江学者，国家自然科学基金委员会杰出青年基金获得者，国家高层次人才特殊支持计划(“万人计划”)入选者，国家自然科学基金委员会创新群体牵头人。主要研究方向为重大心血管疾病的发病机制。在Circulation、Cell Research、Blood、Circulation Research等权威期刊发表SCI论文100余篇。主持创新群体、国家自然科学基金重点项目、国家杰出青年科学基金等多项课题。获得“中国青年科技奖”和“国家科技部·比尔盖茨基金会创新大挑战——青年科学家奖”等奖励。担任国际基质生物学会常务理事，并担任Circulation Research、Matrix Biology、Cardiovascular Research等期刊编委
  • 基金资助:
    国家自然科学基金(81730010);国家自然科学基金(82100480);国家自然科学基金(31930056);国家自然科学基金(81921001);中国博士后科学基金(2020M680257)

Naringenin inhibits thoracic aortic aneurysm formation in mice with Marfan syndrome

Zhi-qing LI1,Bing YU1,Ze-yu CAI1,Ying-bao WANG1,Xu ZHANG1,Biao ZHOU2,Xiao-hong FANG3,Fang YU1,Yi FU1,Jin-peng SUN1,Wei LI4,Wei KONG1,*()   

  1. 1. Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China
    2. Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
    3. Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
    4. Department of Vascular Surgery, Peking University People's Hospital, Beijing 100044, China
  • Received:2022-06-03 Online:2022-10-18 Published:2022-10-14
  • Contact: Wei KONG E-mail:kongw@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81730010);the National Natural Science Foundation of China(82100480);the National Natural Science Foundation of China(31930056);the National Natural Science Foundation of China(81921001);China Postdoctoral Science Foundation(2020M680257)

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摘要：

目的: 探究柚皮素对马凡综合征胸主动脉瘤的作用。方法: 对马凡综合征模型Fbn1C1039G/+小鼠进行柚皮素灌胃，观察柚皮素对小鼠胸主动脉瘤形成的影响，并在体外利用生物荧光共振能量转移、原子力显微镜、同位素标记配体-受体结合等技术探究柚皮素发挥作用的分子机制。结果: Fbn1C1039G/+小鼠予以柚皮素长期预防性给药(6~26周)或治疗性给药(20~26周)均显著抑制小鼠胸主动脉瘤的扩张和弹力板的断裂。同时，柚皮素喂养可降低小鼠血管壁Smad2和细胞外调节蛋白激酶1/2(extracellular regulating kinase 1/2，ERK1/2)的磷酸化以及基质金属蛋白酶(matrix metalloproteinase, MMP)2/9的表达与活性。机制上，柚皮素处理降低血管紧张素Ⅱ(angiotensin Ⅱ，Ang Ⅱ)受体1(angiotensin Ⅱ type 1 receptor，AT1)下游Gq蛋白介导的蛋白激酶C(protein kinase C，PKC)和ERK1/2的磷酸化、钙离子信号和活化T细胞核因子(nuclear factor of activated T-cells, NFAT)信号，同时柚皮素可降低Ang Ⅱ引起的AT1受体内化及β-抑制蛋白-2与AT1受体的结合，并拮抗与AT1的配体-受体结合；柚皮素可以降低转化生长因子-β(transforming growth factor-β，TGF-β)信号通路下游基因的表达，并显著降低Fbn1C1039G/+小鼠血浆中过高的TGF-β水平。血小板是体内TGF-β的主要储存细胞，而柚皮素处理可以抑制凝血酶引起的血小板激活，减轻Fbn1C1039G/+小鼠的血小板活化程度，并降低血小板分泌TGF-β的水平。结论: 柚皮素可能通过抑制AT1受体信号及减少TGF-β产生从而抑制马凡综合征胸主动脉瘤的发生与发展。

关键词: 柚皮素, 马凡综合征, 胸主动脉瘤, 血管紧张素Ⅱ受体1, 转化生长因子-β

Abstract:

Objective: To identify whether naringenin plays a protective role during thoracic aneurysm formation in Marfan syndrome. Methods: To validate the effect of naringenin, Fbn1C1039G/+ mice, the mouse model of Marfan syndrome, were fed with naringenin, and the disease progress was evaluated. The molecular mechanism of naringenin was further investigated via in vitro studies, such as bioluminescence resonance energy transfer (BRET), atomic force microscope and radioligand receptor binding assay. Results: Six-week-old Fbn1C1039G/+ mice were fed with naringenin for 20 weeks. Compared with the control group, naringenin significantly suppressed the aortic expansion [Fbn1C1039G/+ vs. Fbn1C1039G/++naringenin: (2.49±0.47) mm, n=18 vs. (1.87±0.19) mm, n=22, P < 0.05], the degradation of elastin, and the expression and activity of matrix metalloproteinase 2 (MMP2) and MMP9 in the ascending aorta of Fbn1C1039G/+ mice. Besides, treatment with naringenin for 6 weeks also attenuated the disease progress among the 20-week-old Fbn1C1039G/+ mice with established thoracic aortic aneurysms [Fbn1C1039G/+ vs. Fbn1C1039G/++naringenin: (2.24±0.23) mm, n=8 vs. (1.90±0.17) mm, n=8, P < 0.05]. To understand the underlying molecular mechanisms, we examined the effects of naringenin on angiotensin Ⅱ type 1 receptor (AT1) signaling and transforming growth factor-β (TGF-β) signaling respectively, which were the dominant signaling pathways contributing to aortopathy in Marfan syndrome as previously reported. The results showed that naringenin decreased angiotensin Ⅱ (Ang Ⅱ)-induced phosphorylation of protein kinase C (PKC) and extracellular regulating kinase 1/2 (ERK1/2) in HEK293A cell overexpressing AT1 receptor. Moreover, naringenin inhibited Ang Ⅱ-induced calcium mobilization and uclear factor of activated T-cells (NFAT) signaling. The internalization of AT1 receptor and its binding to β-arrestin-2 with Ang Ⅱ induction were also suppressed by naringenin. As evidenced by atomic force microscope and radioligand receptor binding assay, naringenin inhibited Ang Ⅱ binding to AT1 receptor. In terms of TGF-β signaling, we found that feeding the mice with naringenin decreased the phosphorylation of Smad2 and ERK1/2 as well as the expression of TGF-β downstream genes. Besides, the serum level of TGF-β was also decreased by naringenin in the Fbn1C1039G/+ mice. Furthermore, we detected the effect of naringenin on platelet, a rich source of TGF-β, both in vivo and in vitro. And we found that naringenin markedly decreased the TGF-β level by inhibiting the activation of platelet. Conclusion: Our study showed that naringenin has a protective effect on thoracic aortic aneurysm formation in Marfan syndrome by suppressing both AT1 and TGF-β signaling.

Key words: Naringenin, Marfan syndrome, Thoracic aortic aneurysm, Angiotensin Ⅱ type 1 receptor (AT1), Transforming growth factor-β (TGF-β)

中图分类号: 

  • R33

图1

柚皮素抑制Fbn1C1039G/+小鼠胸主动脉瘤的形成"

图2

柚皮素延缓Fbn1C1039G/+小鼠已发生的胸主动脉瘤的进一步扩张"

图3

柚皮素抑制血管紧张素Ⅱ-AT1信号通路"

图4

柚皮素拮抗血管紧张素Ⅱ与AT1的结合"

图5

柚皮素在体和体外抑制TGF-β信号通路的激活"

图6

柚皮素抑制血小板分泌TGF-β"

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ISSN 1671-167X
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