Multi-Omics and Experimental Validation Reveal the Protective Effect of Paeoniflorin Against Coronary Heart Disease
Ying Yang1, Xiang Li1, Wenjing Zong1
1Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Insights
Paeoniflorin (PA) effectively treats coronary heart disease (CHD) by targeting the C3-Cfd-C3aR axis to reduce inflammation, apoptosis, and platelet activation, while also improving metabolic disorders in mice.
Area of Science:
- Cardiovascular Pharmacology
- Natural Product Chemistry
- Systems Biology
Background:
- Coronary heart disease (CHD) presents significant global health challenges due to complex pathology.
- Paeoniflorin (PA), from Ranunculaceae plants, shows cardiovascular protective potential, but its anti-CHD mechanisms and targets are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms and regulatory networks of Paeoniflorin (PA) in treating coronary heart disease (CHD) using a multi-omics approach.
Main Methods:
- Established a mouse model of CHD and employed label-free quantitative proteomics and metabolomics.
- Utilized molecular docking to assess PA's binding affinity with key identified targets.
Main Results:
- PA improved cardiac function, reduced myocardial injury/fibrosis, and regulated lipid metabolism in CHD mice.
- Proteomics identified the C3-Cfd-C3aR axis as a core hub, with PA downregulating C3, Cfd, C3aR, BTK, ITGA2B/ITGB3, inhibiting inflammation and apoptosis.
- Metabolomics revealed PA reversed 57 abnormal metabolites, impacting pathways like GABAergic synapse and endocannabinoid signaling.
Conclusions:
- PA exerts anti-CHD effects via multi-target, multi-pathway synergism, primarily by inhibiting the C3-Cfd-C3aR axis to reduce inflammation, apoptosis, and platelet activation.
- PA also addresses metabolic dysregulation, supporting its potential as a multi-target therapeutic for CHD.
Abstract:
Coronary heart disease (CHD) is a global cardiovascular disease with high morbidity and mortality, and its complex pathological mechanism poses great challenges to clinical prevention and treatment. Paeoniflorin (PA), a monoterpene glycoside active ingredient from Ranunculaceae plants, has shown potential in cardiovascular protection, but its specific anti-CHD molecular targets and systematic regulatory networks remain unclear. In this study, a mouse model of CHD was established, and a multi-omics strategy combining label-free quantitative proteomics and metabolomics was adopted to explore the mechanism of PA in treating CHD. The results showed that PA significantly improved cardiac function, alleviated myocardial pathological injury and fibrosis, and regulated lipid metabolism in CHD model mice, with the high-dose group showing the optimal effect. Proteomic analysis identified 51 key differentially expressed proteins (DEPs) reversed by PA, which were mainly enriched in complement and coagulation cascades, and neutrophil extracellular trap formation pathways, with the C3-Cfd-C3aR signaling axis as the core hub. Further verification confirmed that PA could downregulate the expression of C3, Cfd, C3aR, and their downstream molecule BTK, thereby inhibiting myocardial inflammatory response and cardiomyocyte apoptosis. In addition, PA downregulated the expression of platelet activation markers ITGA2B/ITGB3. Metabolomic analysis revealed that PA reversed 57 abnormal metabolites in CHD mice, which were enriched in GABAergic synapse, retrograde endocannabinoid signaling and other pathways. Molecular docking confirmed that PA could stably bind to C3, Cfd, C3aR, BTK, and ITGA2B/ITGB3 with strong binding activity. In conclusion, PA exerts anti-CHD effects through a multi-target and multi-pathway synergism, mainly by targeting the C3-Cfd-C3aR axis to inhibit inflammation, apoptosis and platelet activation, and regulating metabolic disorders. This study provides experimental evidence and theoretical support for the clinical application of PA as a multi-target therapeutic drug for CHD.
