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Shexiang Tongxin dropping pill protects against isoproterenol-induced myocardial ischemia in vivo and in vitro.

ABSTRACT: Shexiang Tongxin dropping pill (STDP) is a formulae of Chinese Medicine commonly used to treating angina pectoris in China. However, its mechanism of action is still yet unclear. This study investigated the roles of STDP on myocardial ischemia injury. We constructed a rat model of myocardial injury (isoproterenol subcutaneous injection, i.h, 85 mg/kg/day for 2 days), and compared among 4 groups: CON (control), ISO (ischemic injury model), MET (metoprolol), and STDP. Serum contents of Troponin I (cTnI), creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), alpha-hydroxybutyric dehydrogenase (?-HBD), and Aspartate Aminotransferase were detected and five STDP doses (1, 10, 100, 1000 and 10000 mg/kg/day) were chosen to obtain a dose-response curve. Western-blot was used to detect phosphorylations of extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (AKT), and camodulin kinase II (CamkII). Furthermore, an ERK1/2 inhibitor PD98059, a phosphatidylinositol-3-kinase inhibitor, LY294002, and a CamKII inhibitor, KN-93 were administered i.h.

Results

cTnI, CK, CK-MB, ?-HBD, and LDH were significantly lower in STDP than ISO (P<0.05). STDP exhibited a dose-dependent effect with a half maximal inhibitory concentration of 42 mg/kg/day. Phosphorylation of ERK1/2 was enhanced in the STDP group (vs. ISO, P<0.05), while AKT and CamkII were not changed. Further, the protective effects of STDP were offset by PD98059 administration i.h. In conclusion, STDP protected against the ISO-induced myocardial ischemic injury via an ERK1/2 signaling pathway, which provided a mechanism to support clinical applications of STDP as treatment for ischemic heart disease.

SUBMITTER: Qi J

PROVIDER: S-EPMC5752495 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Shexiang Tongxin dropping pill protects against isoproterenol-induced myocardial ischemia <i>in vivo</i> and <i>in vitro</i>.

Qi Jianyong J Pan Wenjun W Tan Yafang Y Luo Jiaru J Fan Dancai D Yu Juan J Wu Jiashin J Zhang Minzhou M

Oncotarget 20171114 65

Shexiang Tongxin dropping pill (STDP) is a formulae of Chinese Medicine commonly used to treating angina pectoris in China. However, its mechanism of action is still yet unclear. This study investigated the roles of STDP on myocardial ischemia injury. We constructed a rat model of myocardial injury (isoproterenol subcutaneous injection, i.h, 85 mg/kg/day for 2 days), and compared among 4 groups: CON (control), ISO (ischemic injury model), MET (metoprolol), and STDP. Serum contents of Troponin I ...[more]

PMID: 29312582

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Project description:Background: Chronic heart failure (CHF) is a major public health problem with high mortality and morbidity worldwide. Shexiang Tongxin Dropping Pill (STDP) is a widely used traditional Chinese medicine preparation for coronary heart disease and growing evidence proves that STDP exerts beneficial effects on CHF in the clinic. However, the mechanism of its effect on CHF still yet to be deciphered. Objective: This study aimed to elucidate the potential pharmacological mechanism of STDP against CHF by integrating network pharmacology analysis and whole-transcriptome sequencing. Methods: First, the mouse model of CHF was established by the transverse aortic constriction (TAC) surgery, and the efficacy of STDP against CHF was evaluated by assessing the alterations in cardiac function, myocardial fibrosis, and cardiomyocyte hypertrophy with echocardiography, Masson's trichrome staining, and wheat germ agglutinin staining. Next, a CHF disease network was constructed by integrating cardiovascular disease-related genes and the transcriptome sequencing data of mouse heart tissue, which was used to explore the underlying mechanism of action of STDP in CHF. Then, the key targets involved in the effects of STDP on CFH were determined by network analysis algorithms, and pathway enrichment analysis was performed to these key genes. Finally, important targets in the critical pathway were verified in vivo. Results: STDP administration (86 mg/kg/d) obviously improved cardiac function, relieved cardiomyocyte hypertrophy, and ameliorated myocardial fibrosis in CFH mice. Moreover, STDP significantly reversed the imbalanced genes that belong to the disease network of CHF in mice with TAC, and the number of genes with the reverse effect was 395. Pathway analysis of the crucial genes with recovery efficiency revealed that pathways related to fibrosis and energy metabolism were highly enriched, while TGF-β pathway and ERK/MAPK pathway were predicted to be significantly affected. Consistently, validation experiments confirmed that inhibiting ERK/MAPK and TGF-β signaling pathways via reduction of the phosphorylation level of Samd3 and ERK1/2 is the important mechanism of STDP against CHF. Conclusion: Our data provided strong evidence that STDP has great potential for the treatment of CHF and the mechanisms are mainly related to inhibition of ERK/MAPK and TGF-β signaling pathways.

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