丹参多酚酸盐改善扩张性心肌病心肌功能的作用机制

doi:10.7503/cjcu20150984

高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (5): 844.doi: 10.7503/cjcu20150984

丹参多酚酸盐改善扩张性心肌病心肌功能的作用机制

王曦烨^1,², 单晓彤³, 王伊林³, 李丹^1,², 赵明³(), 许良^1,²()

1. 内蒙古民族大学化学化工学院, 通辽 028042
2. 天然产物化学及功能分子合成自治区重点实验室, 通辽 028042
3. 内蒙古民族大学附属医院, 通辽 028042

收稿日期:2015-12-26 出版日期:2016-05-10 发布日期:2016-04-07
作者简介:联系人简介: 许良, 男, 博士, 教授, 主要从事天然产物化学研究. E-mail:nmgxl66@163.com
赵明, 男, 博士, 主任医师, 主要从事心血管疾病研究. E-mail: langzhe73@163.com
基金资助:
国家自然科学基金(批准号: 81560702, 81260682)资助

Mechanism of Salvia Miltiorrhiza on the Improvement of Myocardial Function in Patients with Dilated Cardiomyopathy^†

WANG Xiye^1,², SHAN Xiaotong³, WANG Yilin³, LI Dan^1,², ZHAO Ming^3,^*(), XU Liang^1,^2,^*()

1. College of Chemistry and Chemical Engineering, Inner Mongolia University for the Nationalities, Tongliao 028042, China
2. Key Laboratory of Natural Product Chemistry and Functional Molecular Synthetic of Autonomous Region, Tongliao 028042, China
3. Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao 028042, China

Received:2015-12-26 Online:2016-05-10 Published:2016-04-07
Contact: ZHAO Ming,XU Liang E-mail:langzhe73@163.com;nmgxl66@163.com
Supported by:
† Supported by the National Natural Science Foundation of China(Nos;81560702, 81260682)

摘要/Abstract

摘要：

将代谢组学与分子生物学方法相结合, 研究了丹参多酚酸盐治疗扩张性心肌病的作用机制. 采用主成分分析(PCA)法, 分析了健康组、模型组及丹参多酚酸盐给药组大鼠血清代谢轮廓, 采用正交校正的偏最小二乘判别分析(OPLS-DA)法寻找潜在的生物标记物, 共鉴定得到磷酯酰丝氨酸[16∶0/18∶1(9Z)]、溶血磷脂(16∶0)、溶血磷脂[20∶4(5Z,8Z,11Z,14Z)]、溶血磷脂[22∶6(4Z,7Z,10Z,13Z,16Z,19Z)]、胆固醇硫酸酯、胆汁酸、 γ-亚麻酸、二十二碳五烯酸和9'-羧基-γ-生育酚9种潜在的生物标记物. 其中, γ-亚麻酸、二十二碳五烯酸和9'-羧基-γ-生育酚的含量在模型组中下降, 经丹参多酚酸盐治疗后含量上升. 通过Western bloting法和酶联免疫吸附法证实丹参多酚酸盐通过影响体内与γ-亚麻酸和9'-羧基-γ-生育酚相关的超氧化物岐化酶(SOD)、丙二醛(MDA)及其下游Bcl-2和Bax蛋白分子表达量, 从而减少氧化应激所致的心肌细胞凋亡数量, 达到治疗阿霉素所致扩张型心肌病的目的.

关键词: 扩张型心肌病, 丹参多酚酸盐, 代谢组学, 质谱, 氧化应激

Abstract:

Metabonomics combined with molecular biology were used to investigate the mechanisms of anti-dilated cardiomyopathy treated by depside salt from Salvia miltiorrhiza. The serum metabolic profiling of control group, model group and treatment group were analysed by principle component analysis(PCA). The potential biomarkers were selected with the help of orthogonal partial least squares discriminant analysis(OPLS-DA). As results, nine potential biomarkers including the PS[16∶0/18∶1(9Z)], LysoPC(16∶0), LysoPC[20∶4(5Z, 8Z, 11Z, 14Z)], LysoPC[22∶6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)], cholesterol sulfate, taurohyocholate, γ-linolenic acid, docosapentaenoic acid and 9'-carboxy-γ-chromanol were identified respectively. In addition, the relative content of γ-linolenic acid, docosapentaenoic acid and 9'-carboxy-γ-chromanol decreased in the model group, while increased in the treatment group. With the help of western bloting and enzyme-linked immunosorbent method, we confirmed that the depside salt from Salvia miltiorrhiza influenced the expression levels of superoxide disproportionation(SOD), malondialdehyde(MDA), Bcl-2 and Bax protein molecule(the proteins mentioned above were related with γ-linolenic acid and 9'-carboxyl-γ-tocopherol), and then reduced the amount of the apoptosis myocardial cell induced by oxidative stress, and treated the the dilated cardiomyopathy caused by adriamycin finally.

Key words: Dilated cardiomyopathy, Salvia miltiorrhiza, Metabonomics, Mass spectrometry, Oxidative stress

中图分类号:

O657

TrendMD:

王曦烨, 单晓彤, 王伊林, 李丹, 赵明, 许良. 丹参多酚酸盐改善扩张性心肌病心肌功能的作用机制. 高等学校化学学报, 2016, 37(5): 844.

WANG Xiye, SHAN Xiaotong, WANG Yilin, LI Dan, ZHAO Ming, XU Liang. Mechanism of Salvia Miltiorrhiza on the Improvement of Myocardial Function in Patients with Dilated Cardiomyopathy^†. Chem. J. Chinese Universities, 2016, 37(5): 844.

图/表 9

Fig.1 Heart color doppler ultrasound of control group(A), model group(B) and treatment group(C)

Table 1 Effect of salvianolate miltiorrhiza on ventricular structure and ejection fraction in rats with dilated cardiomyopathy

Group	LVIDd/mm	LVSd/mm	LVPWDd/mm	LVEF(%)
C	4.73±0.41^**	1.74±0.1^**	2.1±0.33^**	85.5±3.23^**
M	5.83±0.59	2.08±0.19	1.73±0.07	70.4±5.69
T	5.26±0.33^**	1.99±0.18^**	1.91±0.09^**	76.2±3.19^**

Fig.2 Base peak intensity chromatograms(BPI) under the ESI+ mode(A, C, E) and ESI- mode(B, D, F) (A), (B) Control group; (C), (D) model group; (E), (F) treatment group.

Fig.3 PCA score plots obtained from the metabolic profiles of the control group, model group and treatment group under positive(A) and negative ion modes(B)

Fig.4 OPLS-DA score plots(A, C) and S-plots(B, D) obtained from the metabolic profiles of the control group and model group under positive(A, B) and negative ion modes(C, D)

Table 2 Potential biomarkers between control group and model group

t_R/min	Measured mass	10⁶Mass deviation	MS², m/z	Chemical formula	Compound	ESI mode
6.89	762.5300	2.6	745.5, 265.3, 239.2, 88.0	C₄₀H₇₆NO₁₀P	PS[16∶0/18∶1(9Z)]	+
4.56	496.3406	1.6	330.1	C₂₄H₅₀NO₇P	LysoPC(16∶0)	+
4.44	544.3402	0.7	378.2	C₂₈H₅₀NO₇P	LysoPC[20∶4	+
					(5Z,8Z,11Z,14Z)]
4.45	568.3394	0.7	402.7	C₃₀H₅₀NO₇P	LysoPC[22∶6	+
					(4Z,7Z,10Z,13Z,16Z,19Z)]
5.97	465.3038	1.3	97.1	C₂₇H₄₆O₄S	Cholesterol sulfate	-
3.66	514.2833	2.1	498.5, 480.6, 462.6	C₂₆H₄₅NO₇S	Taurohyocholate	-
4.28	277.2167	2.2	93.2, 79.4, 67.3, 55.6	C₁₈H₃₀O₂	Gamma-Linolenic acid	-
4.64	329.2481	1.5	271.2	C₂₂H₃₄O₂	Docosapentaenoic acid	-
4.96	375.2533	2.1	344.2, 288.6, 275.3, 101.5	C₂₃H₃₆O₄	9'-Carboxy-γ-chromanol	-

Fig.5 Heatmap of metabolites between control(C) group, model(M) group and treatment(T) groupa. γ-linolenic acid; b. docosapentaenoic acid; c. 9'-carboxy-γ-chromanol.

Fig.6 Expression levels of MDA(A) and SOD(B) protein of rats left ventricular myocardial tissue in control group, model group and treatment group*P<0.05, **P<0.01(vs. model group).

Fig.7 Western blot analysis(A) and expression levels(B) of Bcl-2 and Bax protein of rats left ventricular myocardial tissue in control group, model group and treatment group**P<0.01(vs. model group).

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丹参多酚酸盐改善扩张性心肌病心肌功能的作用机制

Mechanism of Salvia Miltiorrhiza on the Improvement of Myocardial Function in Patients with Dilated Cardiomyopathy^†

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丹参多酚酸盐改善扩张性心肌病心肌功能的作用机制

Mechanism of Salvia Miltiorrhiza on the Improvement of Myocardial Function in Patients with Dilated Cardiomyopathy†

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Mechanism of Salvia Miltiorrhiza on the Improvement of Myocardial Function in Patients with Dilated Cardiomyopathy^†