Regulation of phospholipid peroxidation signaling by a traditional Chinese medicine formula for coronary heart disease.

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  • Additional Information
    • Source:
      Publisher: Urban & Fischer Verlag Country of Publication: Germany NLM ID: 9438794 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1618-095X (Electronic) Linking ISSN: 09447113 NLM ISO Abbreviation: Phytomedicine Subsets: MEDLINE
    • Publication Information:
      Publication: Stuttgart : Urban & Fischer Verlag
      Original Publication: Stuttgart ; New York : G. Fischer, c1994-
    • Subject Terms:
      Coronary Disease*/drug therapy ; Drugs, Chinese Herbal*/pharmacology ; Myocardial Ischemia*/drug therapy; Rats ; Mice ; Animals ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; NADP/therapeutic use ; Phospholipids
    • Abstract:
      Background: Phospholipid peroxidation signaling was recently revealed as a novel pathological mechanism of coronary heart disease (CHD), and small molecules involved in this redox-metabolic pathway are suggested as the potential anti-CHD drugs. Danlou Tablet (DLT), a famous traditional Chinese medicine (TCM) formula characterized by multi-component and multi-target regulation, is widely used in the clinical treatment of CHD by regulating lipid metabolism. However, little information is available addressing the corresponding pharmacological mechanisms and associated active components of DLT.
      Purpose: To study whether phospholipid peroxidation involves a novel mechanism of DLT for the therapeutic effect of CHD and to explain the essential active components.
      Methods: Firstly, the HPLC fingerprint was constructed to ensure the controllability of the quality of DLT. Then, a CHD animal model with the characteristics of lipid disorder and myocardial ischemia was established by a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation. The therapeutic effect of DLT was further evaluated based on the results of the rat survival rate, cardiac function, cardiac histopathology, and myocardial ischemia indicators. Correspondingly, whether DLT can regulate the key indicators (ALOX15, GPX4, MDA, GSH, and NADPH) of the phospholipid peroxidation pathway was investigated, and Alox15 -/- mice have been applied to confirm the mechanism of DLT. Finally, the target-mediated characterization strategy based on ALOX15, including the integration of in vivo component characterization, network pharmacology, molecular docking analysis, and activity verification, has been further implemented to reveal the key bio-active components in DLT.
      Results: In this study, a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation was utilized to generate a CHD model, and DLT significantly improved the cardiac dysfunction and reduced the myocardial cell death susceptibility. Further results revealed that DLT reversed the protein expression of ALOX15 and GPX4, the key proteins of phospholipid peroxidation pathways, which subsequently influenced the parameters of phospholipid peroxidation (MDA, GSH, and NADPH). The ALOX15 knockout transgenic animal model confirmed that Alox15 -/- mice lost their cardioprotective effects with DLT, suggesting that DLT exerted therapeutic effects on CHD by regulating ALOX15-mediated phospholipid peroxidation. Finally, the target-mediated characterization strategy identified that daidzein is an active component in DLT against CHD by modulating ALOX15.
      Conclusion: Innovatively, ALOX15-mediated phospholipid peroxidation was identified as one of the critical mechanisms of DLT exerting cardioprotective effects. Our findings elucidate a novel mechanism of DLT and provide some new drug evaluation targets and therapeutic strategies for CHD.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2023 Elsevier GmbH. All rights reserved.)
    • Contributed Indexing:
      Keywords: ALOX15; Coronary heart disease; Daidzein; Danlou tablet; Phospholipid peroxidation; Traditional Chinese medicine
    • Accession Number:
      53-59-8 (NADP)
      0 (Drugs, Chinese Herbal)
      0 (Phospholipids)
    • Publication Date:
      Date Created: 20230317 Date Completed: 20230426 Latest Revision: 20230426
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.phymed.2023.154749
    • Accession Number:
      36931097