Abstract
Background: Yixinshu Capsules (YXSC) are widely used in Chinese medicine for the treatment of cardiovascular diseases. However, the therapeutic mechanisms of action are not well understood. Method: In this study, a metabonomic approach based on integrated UPLC-Q/TOF-MS technique and MALDI-MS was utilized to explore potential metabolic biomarkers that may help increase the understanding of heart failure (HF) and in order to assess the potential mechanisms of YXSC against HF. Plasma metabolic profiles were analyzed by UPLC-Q/TOF-MS with complementary hydrophilic interaction chromatography and reversed-phase liquid chromatography. Moreover, time-course analysis at the 2nd, 4th, and 10th week after permanent occlusion was conducted. In an effort to identify a more reliable potential metabolic marker, common metabolic markers of the 2nd, 4th, and 10th week were selected through multivariate data analysis. Furthermore, MALDI-MS was applied to identify metabolic biomarkers in the blood at apoptotic positions of heart tissues. Results: The results showed that HF appeared at the fourth week after permanent occlusion based on echocardiographic assessment. Clear separations were observed between the sham and model group by loading plots of orthogonal projection to latent structure discrimination analysis (OPLS-DA) at different time points after permanent occlusion. Potential markers of interest were extracted from the combining S-plots, variable importance for the projections values (VIP > 1), and t-test (p < 0.05). Twenty-one common metabolic markers over the course of the development and progression of HF after permanent occlusion were identified. These were determined to be mainly related to disturbances in fatty acids, phosphatidylcholine, bile acids, amino acid metabolism, and pyruvate metabolism. Of the metabolic markers, 16 metabolites such as palmitoleic acid, arachidonic acid, and lactic acid showed obvious changes (p < 0.05) and a tendency for returning to baseline values in YXSC-treated HF rats at the 10th week. Moreover, four biomarkers, including palmitoleic acid, palmitic acid, arachidonic, acid and lactic acid, were further validated at the apoptotic position of heart tissue using MALDI-MS, consistent to the variation trends in the plasma. Conclusions: Taken in concert, our proposed strategy may contribute to the understanding of the complex pathogenesis of ischemia-induced HF and the potential mechanism of YXSC.
Highlights
Heart failure (HF), a common clinical syndrome, is commonly associated with high morbidity and, if survived, may result in lifelong and often devastating health conditions (Doenst et al, 2013; Jackson et al, 2015; Ponikowski et al, 2016)
The results showed that HF appeared at the fourth week after permanent occlusion based on echocardiographic assessment
Clear separations were observed between the sham and model group by loading plots of orthogonal projection to latent structure discrimination analysis (OPLS-DA) at different time points after permanent occlusion
Summary
Heart failure (HF), a common clinical syndrome, is commonly associated with high morbidity and, if survived, may result in lifelong and often devastating health conditions (Doenst et al, 2013; Jackson et al, 2015; Ponikowski et al, 2016). As the end stage of various heart diseases, HF manifestation is characterized with architectural changes or functional disorders, including changes in electrophysiology, inflammatory responses, oxidative stress, energy metabolism, etc. Traditional Chinese medicine (TCM) has long been practiced using multiple components to treat as well as prevent various complex and refractory disease states. Previously conducted studies have shown that YXSC, as a standardized product, has been able to reduce mitochondrial-mediated apoptosis (Zhao et al, 2016), oxidative stress injury (Zhang et al, 2017), and myocardial dysfunction (Zhang et al, 2017). Even though numerous clinical trials have shown that YXSC exhibits a protective function against HF, the mechanism of YXSC used as a treatment option for HF remains unclear. Yixinshu Capsules (YXSC) are widely used in Chinese medicine for the treatment of cardiovascular diseases. The therapeutic mechanisms of action are not well understood
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