上海交通大学学报(医学版)

• 论著(基础研究) • 上一篇    下一篇

S1P受体激动剂FTY720在大鼠非梗死区心肌组织中的作用

刘晔弘1,2, 范骎1, 张凤如1 ,陆林1, 沈卫峰1, 陶蓉1   

  1. 1.上海交通大学 医学院附属瑞金医院心血管内科, 上海 200025; 2.同济大学附属东方医院心血管内科, 上海 200120
  • 出版日期:2016-09-28 发布日期:2016-10-31
  • 通讯作者: 陶蓉, 电子信箱: rongtao@hotmail.com。
  • 作者简介:刘晔弘(1986—), 女, 住院医师, 硕士生, 电子信箱: cindy_lyh_hch@hotmail.com。
  • 基金资助:

    国家自然科学基金(81070178,813702560);上海市科委重大基础研究项目(12JC1406300);上海市教育委员会高峰高原学科建设计划(20152205)

Effect of S1P-receptor agonist FTY720 in non-infarcted myocardium of rats

LIU Ye-hong1,2, FAN Qin1, ZHANG Feng-ru1, LU Lin1, SHEN Wei-feng1, TAO Rong1   

  1. 1.Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 2.Department of Cardiology, Dong Fang Hospital, Tong Ji University, Shanghai 200120, China
  • Online:2016-09-28 Published:2016-10-31
  • Supported by:

    National Natural Science Foundation of China, 81070178,813702560; Shanghai Science and Technology Key Project Grant, 12JC1406300; Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support, 20152205

摘要:

目的·分析S1P受体激动剂FTY720对大鼠心肌不同亚型S1P受体表达的影响,以及梗死后的心肌中主要与FTY720结合的S1P受体亚型,并探讨这一过程对于心肌梗死后非梗死区存活心肌的保护作用。方法·建立SD大鼠心肌梗死模型,并设置对应假手术组,分别进行生理盐水、低剂量(0.04 mg/kg)FTY720和高剂量(0.4 mg/kg)FTY720处理,处理4周后进行测定,比较各组间心功能的差异;应用实时定量PCR检测心肌梗死发生前和发生后心肌组织中不同亚型S1P受体的表达情况,分析高剂量FTY720对其表达的影响;应用组织化学染色分析高剂量FTY720处理对非梗死区心肌组织的一般结构、纤维化程度以及细胞凋亡的影响;应用Western blotting检测高剂量FTY720处理对非梗死区心肌磷酸化AKT和磷酸化ERK的表达水平。结果·正常大鼠心肌组织中主要表达S1P1受体,其次是S1P3受体。心肌梗死4周后非梗死区中S1P受体的表达水平明显下降,而经高剂量FTY720处理后能显著提高S1P1和S1P3受体的表达水平。同样,经FTY720处理后,心肌梗死后存活心肌的病理改变及重构减弱,纤维化程度减轻,心肌细胞凋亡减少。此外,FTY720处理能使非梗死区中AKT和ERK蛋白的磷酸化水平显著上升。结论·作为S1P受体激动剂,FTY720可能作用于心肌细胞上的S1P1和S1P3受体,激活AKT和ERK通路,从而对心肌梗死后非梗死区的存活心肌发挥保护作用。

关键词: 1-磷酸鞘氨醇, FTY720, 心肌梗死

Abstract:

Objective·To analyze the effect of S1P-receptor agonist FTY720 on the expression of different receptor subtypes of S1P, explore the major receptor subtype of S1P that binds FTY720 in cardiomyocytes of rats with myocardial infarction (MI), and further investigate the protective function on non-infarcted myocardium after MI. Methods·The SD rat model of MI was constructed and SD rats were randomly allocated to sham and MI groups, both of which were further divided into three groups treated with saline, low dosage (0.04 mg/kg) of FTY720, and high dosage (0.4 mg/kg) of FTY720. Tests were performed to compare cardiac function between different groups four weeks after treatment. RT-PCR was used to measure the expressions of S1P1, S1P2, and S1P3 receptors in myocardium before and after MI and to analyze the effect of high dosage of FTY720 on the expression of S1P receptors. Histochemical staining was used to analyze the effects of FTY720 treatment on myocardial structure, interstitial fibrosis, and cell apoptosis in non-infarcted myocardium. Western blotting was conducted to detect the effect of high dosage of FTY720 on the expressions of phosphorylated AKT and ERK in non-infarcted myocardium. Results·In normal myocardium of rats without MI, S1P1 receptor was the most predominantly expressed subtype, followed by S1P3 subtype. Four weeks after MI, the expressions of S1P receptors were significantly reduced, while high dosage FTY720 treatment could remarkably elevate the expressions of S1P1 and S1P3. Similarly, FTY720 treatment could reduce pathological changes in non-infarcted myocardial tissues after MI, including cardiac remodeling, fibrosis, and cell apoptosis. Moreover, the levels of phosphorylated AKT and ERK were significantly elevated after FTY720 treatment. Conclusion·As an important agonist of S1P receptors, FTY720 may activate the AKT and ERK pathways through acting on S1P1 and S1P3 receptors in cardiomyocytes, so as to protect the non-infarcted myocardium after MI.

Key words: sphingosine 1-phosphate; FTY720, myocardial infarction