Dataset Information

Shexiang Tongxin Dropping Pill Improves Peripheral Microvascular Blood Flow via Cystathionine-?-Lyase.

ABSTRACT: BACKGROUND To explore the protective effects of Shexiang Tongxin Dropping Pill (STP) in improving peripheral microvascular dysfunction in mice and to explore the involved mechanism. MATERIAL AND METHODS A peripheral microvascular dysfunction model was established by combined myocardial infarction (MI) and lipopolysaccharide (LPS) injection in mice. Then, the mice were randomized into a model group (n=10) or an STP group (n=10), which were treated with normal saline and STP, respectively. The cremaster muscle microvascular blood flow velocity and numbers of leukocytes adherent to the venular wall were evaluated before and after drug intervention. We assessed the expression of adhesion molecule CD11b and related transcript factor FOXO1 in leukocytes, cystathionine-?-lyase (CSE) mRNA expression in the cremaster muscle, and mitochondrial DNA copy numbers. RESULTS Compared with those of control mice, the cremaster microvascular blood flow velocity, cremaster CSE expression, and mitochondrial DNA copy number in mice from the model group were significantly lower and leukocyte adhesion and CD11b and FOXO1 expression were significantly higher. Intervention with STP could significantly increase the cremaster microvascular flow velocity (0.480±0.010 mm/s vs. 0.075±0.005 mm/s), mRNA expression of cremaster CSE, and mitochondrial DNA copy number, but it inhibited leukocyte adhesion and decreased leukocyte CD11b and FOXO1 expression. CONCLUSIONS STP significantly improved peripheral microcirculation, in which increased CSE expression might be the underlying mechanism.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6716298 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Shexiang Tongxin Dropping Pill Improves Peripheral Microvascular Blood Flow via Cystathionine-γ-Lyase.

Zhang Yanda Y Zhao Jian J He Zhiqing Z Shi Shanlan S Liang Chun C Wu Zonggui Z

Medical science monitor : international medical journal of experimental and clinical research 20190822

BACKGROUND To explore the protective effects of Shexiang Tongxin Dropping Pill (STP) in improving peripheral microvascular dysfunction in mice and to explore the involved mechanism. MATERIAL AND METHODS A peripheral microvascular dysfunction model was established by combined myocardial infarction (MI) and lipopolysaccharide (LPS) injection in mice. Then, the mice were randomized into a model group (n=10) or an STP group (n=10), which were treated with normal saline and STP, respectively. The cre ...[more]

PMID: 31437131

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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 molecular mechanism of the therapeutic effects of STDP on CHF remains largely unknown. Objective: This study aimed to elucidate the mechanism of action 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, which was used to explore the underlying mechanism of action of STDP. Then, the key targets involved in the effects of STDP on CHF were determined by network analysis algorithms, and pathway enrichment analysis was performed to these key genes. Finally, important targets in critical pathway were verified in vivo. Results: STDP administration obviously improved cardiac function, relieved cardiomyocyte hypertrophy, and ameliorated myocardial fibrosis in CHF 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 Smad3 and ERK1/2 is the important mechanism of STDP against CHF. Conclusion: Our data demonstrated that STDP can recover the imbalanced CHF network disturbed by the modeling of TAC through the multi-target and multi-pathway manner in mice, and the mechanisms are mainly related to inhibition of ERK/MAPK and TGF-β signaling pathways.

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.

Project description:Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine ?-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.

Project description:Background: The coronary microvascular dysfunction has attracted more and more attention in recent years, but there is still a lack of effective treatment. Shexiang Baoxin Pill is one of the commonly used drugs for the treatment of coronary artery disease in China. More recently, some studies found that it has the effect of improving coronary microvascular function. Objective: To evaluate the effects of Shexiang Baoxin Pill for coronary microvascular function. Methods: Databases including MEDLINE, Web of Science, CNKI, Wanfang, The Cochrane Library, EMbase, VIP and CBM were searched from inception to June 2021 to screen out relevant clinical studies. The 2019 version 2 of the Cochrane risk of bias tool (RoB2) were used to assess the methodological quality of the included studies. RevMan 5.3 software was used for meta-analysis. Results: Eleven studies meeting the criteria were included, with a total of 1,075 patients. The results of meta-analysis showed that compared with conventional treatment alone, combination of Shexiang Baoxin Pill and conventional treatment can further increase the coronary flow reserve (CFR) [mean difference (MD) = 0.43, 95%CI (0.28, 0.58), p < 0.000 01], decrease the index of microvascular resistance (IMR) [MD = -4.23, 95%CI (-5.49, -2.97), p < 0.000 01], increase serum nitric oxide (NO) [MD = 11.96, 95%CI (2.74, 21.18), p = 0.001] and decrease serum hypersensitive C-reactive protein (hs-CRP) [MD = -2.49, 95%CI (-3.08, -1.90), p < 0.000 01], but did not increase the time of duration on the exercise testing (TET) [MD = 3.64, 95%CI (-1.17, 8.45), p = 0.14]. In terms of safety, a total of 10 patients developed adverse reactions in the intervention group and 17 patients developed adverse reactions in the control group. Conclusion: Current evidence suggests that Shexiang Baoxin Pill may be effective in the improvement of coronary microvascular function when used in combination with conventional treatment. However, due to the low quality of the included studies, lack of placebo control and high heterogeneity among different studies, we should take a cautious attitude towards this conclusion. Moreover, the safety of Shexiang Baoxin Pill remains uncertain, more high-quality clinical studies are needed to verify the efficacy and safety of this drug in the future. Systematic Review Registration: [website], identifier [registration number: CRD42021265113].

Dataset Information

Shexiang Tongxin Dropping Pill Improves Peripheral Microvascular Blood Flow via Cystathionine-?-Lyase.

Publications

Shexiang Tongxin Dropping Pill Improves Peripheral Microvascular Blood Flow via Cystathionine-γ-Lyase.

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