Shenzhu Guanxin formula alleviates atherosclerosis in rats via PI3K/Akt pathway inhibition: a comparative study of...

Shenzhu Guanxin Formula (SGF), a traditional Chinese medicinal compound comprising nine classical herbal constituents, has demonstrated clinical efficacy in the treatment of coronary heart disease. However, its bioactive components and mechanistic underpinnings in atherosclerosis (AS) remain elusive. This study aimed to elucidate the anti-atherosclerotic effects, bioactive constituents, therapeutic targets, and underlying mechanisms of both SGF decoction and granule formulations. An atherosclerotic rat model was established using a 16-week high-fat diet, supplemented with vitamin D₃ injections and carotid artery clamping. The anti-atherosclerotic efficacy of varying doses of SGF granules and decoction was assessed by quantifying serum lipid profiles, antioxidant capacity, inflammatory markers, and vascular morphology. Mechanistic insights were explored by integrating network pharmacology with carotid artery transcriptomics, followed by experimental validation in human umbilical vein endothelial cells (HUVECs) treated with SGF-medicated serum. Results indicated that SGF dose-dependently ameliorated atherosclerotic progression in rats, evidenced by improved serum lipid parameters, reduced carotid plaque burden and arterial/hepatic lipid deposition, enhanced antioxidant status (elevated superoxide dismutase and glutathione levels), and decreased concentrations of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α). Western blot analysis revealed downregulation of phosphorylated Akt (p-Akt), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), vascular endothelial growth factor A (VEGF-A), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), along with upregulation of endothelial nitric oxide synthase (eNOS). Integrated network pharmacology and transcriptomic analyses identified 99 putative active components and 243 AS-related targets, highlighting the PI3K-Akt signaling pathway as pivotal. In oxidized low-density lipoprotein (oxLDL)-injured HUVECs, SGF-medicated serum attenuated reactive oxygen species (ROS) generation and suppressed PI3K/Akt activation, thereby supporting the in-silico predictions. In conclusion, both SGF decoction and granule formulations exert comparable anti-atherosclerotic effects in rats, primarily through ameliorating dyslipidemia, inflammation, and plaque burden, largely mediated via inhibition of the PI3K/Akt pathway.