Modeling Principle

The rabbit atherosclerosis model is a SCI gold-standard standardized cardiovascular animal model based on continuous high-fat and high-cholesterol diet intervention combined with mild vascular endothelial injury, which accurately simulates the progressive vascular pathological process of human atherosclerosis. It focuses on the core pathological mechanisms of lipid metabolism disorder, vascular endothelial injury, lipid infiltration and deposition, sustained inflammatory activation and progressive plaque formation, and highly recapitulates the complete pathological progression of clinical atherosclerosis. New Zealand white rabbits have a lipoprotein metabolism pattern highly similar to humans and extremely high sensitivity to high-cholesterol diets. Exogenous cholesterol intake directly breaks bodily lipid homeostasis, causing abnormal surge of serum total cholesterol, triglyceride and low-density lipoprotein, as well as a significant decrease in high-density lipoprotein, forming a typical hyperlipidemia state. Excessive lipids infiltrate the vascular endothelial space with blood circulation, damage the integrity of the vascular endothelial barrier, and induce endothelial cell apoptosis and dysfunction. Meanwhile, it continuously activates the NF-κB inflammatory pathway, promotes the massive release of pro-inflammatory factors such as TNF-α, IL-6 and IL-1β, and induces persistent chronic low-grade inflammation in the vascular wall. The inflammatory microenvironment further aggravates oxidative modification of lipids to form oxidized low-density lipoprotein (ox-LDL), which recruits a large number of macrophages to phagocytose lipids and transform into foam cells. Continuous deposition of lipids, foam cells and inflammatory cells in the vascular intima gradually forms lipid streaks, fibrous plaques and mature atherosclerotic plaques, and eventually leads to typical atherosclerotic phenotypes such as vascular intimal thickening, lumen stenosis and decreased vascular elasticity. With stable plaque formation, clear pathological hierarchy and high phenotypic uniformity, this model is an internationally recognized gold-standard model for researching atherosclerosis pathogenesis, lipid metabolism regulation, vascular endothelial protection and anti-atherosclerotic new drug screening, and is widely applicable to basic cardiovascular pharmacological research and preclinical translational evaluation.

Modeling Success Criteria

Macroscopic Vascular Phenotypes

The aortic vascular wall of rabbits in the blank control group was smooth, flexible, with intact and transparent intima, no lipid adhesion and no plaque protrusion. The inner aortic wall of rabbits in the model group showed a large number of diffuse yellow-white lipid streaks, punctate and patchy atherosclerotic plaques, with thickened vascular wall, stiff texture and mild lumen stenosis. The lipid deposition was uniformly distributed with typical plaque formation, and the macroscopic phenotype was extremely significantly different from that of the blank group, confirming the preliminary formation of the atherosclerosis model.

Core Serum Lipid Biochemical Indexes

The levels of serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the model group were significantly increased compared with the blank control group, while the level of high-density lipoprotein cholesterol (HDL-C) was significantly decreased, presenting typical pathological hyperlipidemia characteristics and severe lipid metabolism disorder, which fully conforms to the core biochemical mechanism of dyslipidemia in clinical atherosclerosis and serves as the key quantitative gold standard for successful modeling.

Vascular Histopathological Characteristics

HE staining and oil red O staining of aortic blood vessels showed typical atherosclerotic pathological changes: significantly thickened vascular intima, damaged and disordered intimal structure, and a large amount of lipid deposition at the junction of intima and media; massive infiltration and aggregation of foam cells, diffuse distribution of inflammatory cells and significantly increased number of lipid vacuoles, forming clear lipid streaks and early fibrous plaques; disordered arrangement and mild proliferation of smooth muscle cells in the vascular media, which accurately corresponds to the early to mid-stage clinical atherosclerotic pathological phenotypes with stable and typical hierarchical modeling characteristics.

Core Oxidative Stress and Inflammatory Indexes

The contents of ROS, MDA and ox-LDL in serum and aortic tissues of the model group were significantly upregulated, while the activities of antioxidant enzymes SOD and GSH-Px were significantly decreased, resulting in severe vascular oxidative stress imbalance and intense lipid peroxidation damage. Core pro-inflammatory factors (TNF-α, IL-6, IL-1β) and the vascular inflammatory pathway NF-κB were significantly activated, with obvious persistent chronic inflammatory infiltration in the vascular wall, which fully conforms to the interactive pathogenic mechanism of lipid damage-oxidative stress-chronic inflammation in atherosclerosis and serves as the core academic criterion for successful model construction.

Model Advantages

As a SCI-certified exclusive gold-standard large animal model for atherosclerosis, New Zealand white rabbits have highly homologous lipid metabolism with humans, avoiding the natural anti-atherosclerotic defects of rodents. The modeling pathological process, plaque morphology and lipid deposition rules are highly consistent with human clinical lesions. Adopting pure high-fat diet progressive induction, it features a pure modeling mechanism, no surgical trauma interference, extremely low mortality, simple operation and controllable cost. The plaque formation is gradual with clear pathological hierarchy (lipid streak-foam cell-fibrous plaque), excellent intra-group data uniformity and high reproducibility. It accurately focuses on the core pathogenic pathways of lipid disorder, endothelial damage, oxidative inflammation and plaque proliferation, and is perfectly suitable for preclinical pharmacodynamic evaluation of lipid-regulating and plaque-stabilizing, vascular endothelial-protective, anti-oxidative and anti-inflammatory, and anti-atherosclerotic drugs. With strong project innovation and highly recognized data, it is fully applicable for project declaration, master and doctoral theses, high-score SCI publication and cardiovascular translational medical research.

Research Applications

The rabbit atherosclerosis model is corely applied to the research of vascular lesion mechanism induced by lipid metabolism disorder, vascular endothelial injury repair mechanism and arterial plaque formation mechanism mediated by oxidative inflammation. It is specially used for screening and evaluating traditional Chinese medicine compounds, natural active ingredients, small chemical molecules and cardiovascular protective preparations with effects of lipid regulation and reduction, arterial plaque stabilization, vascular endothelial protection, anti-oxidation and anti-inflammation, and vascular remodeling inhibition. It is widely used in the elucidation of atherosclerosis pathogenesis, vascular protection target exploration and preclinical pharmacodynamic and mechanism verification of new anti-atherosclerotic drugs, serving as an essential core standardized large animal model in the fields of cardiovascular pharmacology, vascular biology and lipid metabolism research.

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