Objective To explore the pleiotropic molecular mechanisms by which atorvastatin (Ator) regulates atherosclerosis (AS) in ApoE^－/－ mice.

Methods Thirty 8-week-old male ApoE^－/－ mice were induced to develop atherosclerosis by a high-fat diet. They were randomly assigned to a control group (normal saline), a low-dose Ator group (5 mg/kg·d), and a high-dose Ator group (10 mg/kg·d), and received interventions for 10 weeks. The primary outcome indicators were assessed by Oil Red O and HE staining to measure the area of atherosclerotic plaques. Secondary outcome indicators included serum lipid levels detected by a blood chemical analyzer, Masson and Sirius Red staining combined with polarized light to assess plaque stability indicators (collagen fiber content, fibrous cap thickness), immunohistochemistry to detect the expression of α-smooth muscle actin (α-SMA) and CD68, fluorescence microplate reader to measure reactive oxygen species (ROS) levels, Western blot and RT-qPCR to detect protein and gene expression of inflammation, oxidative stress, apoptosis-related molecules, matrix metallopeptidase 7 (MMP-7), and guanine nucleotide-binding protein subunit α-13 (Gα13).

Results Blood lipids and plaques: Ator reduced serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) levels (P < 0.05), and dose-dependently decreased the area of aortic lipid deposition and plaque area (Control group: plaque area 1.62 ± 0.15 mm², Low-dose group: 1.13 ± 0.06 mm², High-dose group: 0.83 ± 0.07 mm², P < 0.001). Plaque stability: Ator increased collagen fiber content (P < 0.001), increased fibrous cap thickness, upregulated α-SMA expression, and downregulated CD68 expression (P < 0.001). Oxidative stress: Ator remarkably diminished the levels of ROS in arterial tissue and malondialdehyde (MDA) in serum (P < 0.001). Molecular mechanism: Ator downregulated pro-inflammatory factors (tumor necrosis factor-alpha TNF-α, interleukin-6 IL-6), NLRP3, pro-apoptotic proteins (caspase-3, p53), inducible nitric oxide synthase (iNOS), and MMP-7; and upregulated anti-apoptotic protein Bcl-2, antioxidant proteins mitochondrial deacetylase 3 (sirtuin 3, SIRT3)/superoxide dismutase 2 (SOD2), and Gα13 (P < 0.001). The expression trends of these proteins and genes were consistent, with a more significant effect in the high-dose group.

Conclusion Atorvastatin exerts its anti-atherosclerotic effects by regulating blood lipids, inhibiting inflammatory responses, reducing oxidative stress, and regulating apoptosis. It also affects the expression of MMP-7 and Gα13.