Network pharmacology and bioinformatics analysis reveals: NXC improves cardiac lymphangiogenesis through miR-126-3p/SPRED1 regulating the VEGF-C axis to ameliorate post-myocardial infarction heart failure

Abstract

Ethnopharmacological relevance: Cardiac lymphangiogenesis disorder serves as a vital pathological mechanism in post-myocardial infarction heart failure (MI-HF). Nuanxin Capsule (NXC) has been applied in the treatment of MI-HF for more than 20 years and has shown clinical effectiveness in improving cardiac function in MI-HF patients. Nevertheless, the exact mechanisms through which NXC treats MI-HF are still unknown.

Aim of the study: In this research, our aim was to investigate the influence of NXC on cardiac lymphangiogenesis and its mechanism in the treatment of MI-HF.

Methods: The MI-HF mouse model was constructed by ligating the coronary artery. The protective impacts of NXC on cardiac function and fibrosis were appraised through echocardiography, Masson staining, and Western blotting. Cardiac lymphangiogenesis and inflammation were evaluated by RT-qPCR, immunohistochemistry, and Western blotting. UPLC-MS/MS, network pharmacology, and bioinformatics techniques were utilized to investigate the relevant targets and underlying mechanism of NXC in MI-HF. The regulatory effects of NXC on the miR-126-3p/SPRED1 and VEGF-C pathways were analyzed by RT-qPCR, Western blotting, and Dual-luciferase assay. Finally, AAV9-anti-miR-126-3p was injected into MI-HF mice via the tail vein to determine the molecular mechanism of NXC.

Results: Our research results demonstrated that NXC notably improved cardiac function in MI-HF mice, facilitated the formation of cardiac lymphatic vessels, reduced the expression of inflammatory factors, and alleviated myocardial fibrosis. Network pharmacology and bioinformatics analyses further revealed that NXC exerted its cardioprotective effects by promoting cardiac lymphangiogenesis through the modulation of the VEGF-C pathway by miR-126-3p/SPRED1. Dual-luciferase test further confirmed that miR-126-3p has binding to SPRED1. The administration of anti-miR-126-3p effectively negated the cardioprotective effects of NXC in MI-HF mice, as well as its ability to promote lymphangiogenesis, reduce inflammation, and relieve myocardial fibrosis.

Conclusion: The findings of this research indicate that NXC can stimulate the VEGF-C pathway via miR-126-3p/SPRED1 to promote cardiac lymphangiogenesis, thus treating MI-HF. Additionally, the study initially revealed that miR-126-3p affects lymphangiogenesis in MI-HF by regulating the VEGF-C pathway. These results offer valuable insights for the development of cardiovascular drugs targeting MI-HF by leveraging the potential of NXC to enhance cardiac lymphangiogenesis.

Keywords: Cardiac lymphangiogenesis; Nuanxin capsule; Post-myocardial infarction heart failure; VEGF-C; miR-126-3p.