Astragali Radix prevents hypertension in SHRs via suppressing inflammation and modulating serum metabolism: integrated in vivo pharmacological validation, network pharmacology, molecular docking, and metabolomics

Abstract Hypertension is the leading global preventable risk factor for cardiovascular disease (CVD). Astragali Radix (AR), a natural product known for its dual medicinal and nutritional properties, is extensively utilized for preventing hypertension. Nevertheless, the specific ingredients and mechanisms responsible for the antihypertensive effects of AR remain inadequately understood. The present study aims to explore the pharmacological effects, active ingredients, potential targets and mechanisms of AR in preventing hypertension by integrating network pharmacology, metabolomics, molecular docking, and in vivo experimental validation. The results showed that AR reduced blood pressure and alleviated vascular and myocardial damage in spontaneously hypertensive rats (SHRs), as evidenced by the decreased blood pressure, endothelin-1 (ET-1), and angiotensin Ⅱ (Ang Ⅱ), as well as serum cardiac injury markers including creatine kinase (CK), creatine kinase isoenzymes (CK-MB), cardiac troponin Ⅰ (cTnI), and lactate dehydrogenase (LDH). Quercetin and kaempferol might be the primary active ingredients responsible for the antihypertensive effects of AR based on the analysis of network pharmacology. In addition, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were predicted as the core targets of AR in preventing hypertension and enriched in the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. Molecular docking studies revealed that quercetin and kaempferol exhibited strong binding affinities with PI3K and Akt, respectively. In addition, AR suppressed vascular inflammation and activated the PI3K-Akt signaling pathway in SHRs. Furthermore, metabolomics analysis revealed that AR predominantly restored the disorder of serum metabolites in SHRs, particularly those involved in lipid metabolism, amino acid metabolism, and the metabolism of cofactors and vitamins. In conclusion, AR exerts antihypertensive effects on SHRs through inhibiting inflammation mediated by PI3K-Akt signaling pathway and improving metabolic disorders.