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A metabolomic study of rats with doxorubicin-induced cardiomyopathy and Shengmai injection treatment.

Chen Y, Tang Y, Zhang YC, Huang XH, Xie YQ, Xiang Y - PLoS ONE (2015)

Bottom Line: As a result of its multi-component and multi-target nature and comprehensive regulation, the pharmacological mechanisms underlying SMI's effects remain obscure.However, SMI improved cardiac structure and function, as well as the metabolism of the rats with DOX-CM.The metabolic alterations induced via SMI, including the promotion of glycogenolysis, glycolysis, amino acid utilization and antioxidation, suggested that SMI exerts cardioprotective effects by improving energy metabolism and attenuating oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: The Division of Cardiology, Xin Hua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

ABSTRACT
Doxorubicin-induced cardiomyopathy (DOX-CM) is a severe complication of doxorubicin (DOX) chemotherapy. Characterized by cumulative and irreversible myocardial damage, its pathogenesis has not been fully elucidated. Shengmai Injection (SMI), a Traditional Chinese Medicine, may alleviate myocardial injury and improve heart function in the setting of DOX-CM. As a result of its multi-component and multi-target nature and comprehensive regulation, the pharmacological mechanisms underlying SMI's effects remain obscure. The emerging field of metabolomics provides a potential approach with which to explore the pathogenesis of DOX-CM and the benefits of SMI treatment. DOX-CM was induced in rats via intraperitoneal injections of DOX. Cardiac metabolic profiling was performed via gas chromatography/mass spectrometry and ultra-performance liquid chromatography/tandem mass spectrometry. A bioinformatics analysis was conducted via Ingenuity Pathway Analysis (IPA). Eight weeks following DOX treatment, significant cardiac remodeling, dysfunction and metabolic perturbations were observed in the rats with DOX-CM. The metabolic disturbances primarily involved lipids, amino acids, vitamins and energy metabolism, and may have been indicative of both an energy metabolism disorder and oxidative stress secondary to DOX chemotherapy. However, SMI improved cardiac structure and function, as well as the metabolism of the rats with DOX-CM. The metabolic alterations induced via SMI, including the promotion of glycogenolysis, glycolysis, amino acid utilization and antioxidation, suggested that SMI exerts cardioprotective effects by improving energy metabolism and attenuating oxidative stress. Moreover, the IPA revealed that important signaling molecules and enzymes interacted with the altered metabolites. These findings have provided us with new insights into the pathogenesis of DOX-CM and the effects of SMI, and suggest that the combination of metabolomic analysis and IPA may represent a promising tool with which to explore and better understand both heart disease and TCM therapy.

No MeSH data available.


Related in: MedlinePlus

A simplified schematic diagram of the metabolic changes induced by DOX-CM and SMI treatment.The red arrows represent DOX group versus the control group; the green arrows represent the DOX + SMI group versus the DOX group, *p<0.05, 0.05<#p<0.10.
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pone.0125209.g008: A simplified schematic diagram of the metabolic changes induced by DOX-CM and SMI treatment.The red arrows represent DOX group versus the control group; the green arrows represent the DOX + SMI group versus the DOX group, *p<0.05, 0.05<#p<0.10.

Mentions: Compared with the control group, 31 significantly altered metabolites and 19 modestly altered metabolites were observed in the rats with DOX-CM (S3 Table). Among them, 24 metabolites were upregulated, whereas the others were downregulated. These metabolites were primary involved in lipid, amino acid, vitamin and energy metabolism. A simplified schematic diagram of these metabolites is included in Fig 8. To further investigate the interactions among the altered metabolites and explore the possible pathogenesis of DOX-CM, a bioinformatics analysis was performed via an IPA, and a biological network was built by combining the metabolites and the pathways, in which important signaling molecules such as PI3K, AKT, AMPK, ERK, AKC, mTOR and NRF2, as well as enzymes such as SOD, GPX, CAT, GOT, ALT and eNOS, were included (Fig 9).


A metabolomic study of rats with doxorubicin-induced cardiomyopathy and Shengmai injection treatment.

Chen Y, Tang Y, Zhang YC, Huang XH, Xie YQ, Xiang Y - PLoS ONE (2015)

A simplified schematic diagram of the metabolic changes induced by DOX-CM and SMI treatment.The red arrows represent DOX group versus the control group; the green arrows represent the DOX + SMI group versus the DOX group, *p<0.05, 0.05<#p<0.10.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418690&req=5

pone.0125209.g008: A simplified schematic diagram of the metabolic changes induced by DOX-CM and SMI treatment.The red arrows represent DOX group versus the control group; the green arrows represent the DOX + SMI group versus the DOX group, *p<0.05, 0.05<#p<0.10.
Mentions: Compared with the control group, 31 significantly altered metabolites and 19 modestly altered metabolites were observed in the rats with DOX-CM (S3 Table). Among them, 24 metabolites were upregulated, whereas the others were downregulated. These metabolites were primary involved in lipid, amino acid, vitamin and energy metabolism. A simplified schematic diagram of these metabolites is included in Fig 8. To further investigate the interactions among the altered metabolites and explore the possible pathogenesis of DOX-CM, a bioinformatics analysis was performed via an IPA, and a biological network was built by combining the metabolites and the pathways, in which important signaling molecules such as PI3K, AKT, AMPK, ERK, AKC, mTOR and NRF2, as well as enzymes such as SOD, GPX, CAT, GOT, ALT and eNOS, were included (Fig 9).

Bottom Line: As a result of its multi-component and multi-target nature and comprehensive regulation, the pharmacological mechanisms underlying SMI's effects remain obscure.However, SMI improved cardiac structure and function, as well as the metabolism of the rats with DOX-CM.The metabolic alterations induced via SMI, including the promotion of glycogenolysis, glycolysis, amino acid utilization and antioxidation, suggested that SMI exerts cardioprotective effects by improving energy metabolism and attenuating oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: The Division of Cardiology, Xin Hua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

ABSTRACT
Doxorubicin-induced cardiomyopathy (DOX-CM) is a severe complication of doxorubicin (DOX) chemotherapy. Characterized by cumulative and irreversible myocardial damage, its pathogenesis has not been fully elucidated. Shengmai Injection (SMI), a Traditional Chinese Medicine, may alleviate myocardial injury and improve heart function in the setting of DOX-CM. As a result of its multi-component and multi-target nature and comprehensive regulation, the pharmacological mechanisms underlying SMI's effects remain obscure. The emerging field of metabolomics provides a potential approach with which to explore the pathogenesis of DOX-CM and the benefits of SMI treatment. DOX-CM was induced in rats via intraperitoneal injections of DOX. Cardiac metabolic profiling was performed via gas chromatography/mass spectrometry and ultra-performance liquid chromatography/tandem mass spectrometry. A bioinformatics analysis was conducted via Ingenuity Pathway Analysis (IPA). Eight weeks following DOX treatment, significant cardiac remodeling, dysfunction and metabolic perturbations were observed in the rats with DOX-CM. The metabolic disturbances primarily involved lipids, amino acids, vitamins and energy metabolism, and may have been indicative of both an energy metabolism disorder and oxidative stress secondary to DOX chemotherapy. However, SMI improved cardiac structure and function, as well as the metabolism of the rats with DOX-CM. The metabolic alterations induced via SMI, including the promotion of glycogenolysis, glycolysis, amino acid utilization and antioxidation, suggested that SMI exerts cardioprotective effects by improving energy metabolism and attenuating oxidative stress. Moreover, the IPA revealed that important signaling molecules and enzymes interacted with the altered metabolites. These findings have provided us with new insights into the pathogenesis of DOX-CM and the effects of SMI, and suggest that the combination of metabolomic analysis and IPA may represent a promising tool with which to explore and better understand both heart disease and TCM therapy.

No MeSH data available.


Related in: MedlinePlus