Background: Atherosclerosis (AS) is a primary driver of cardiovascular disease. This study aimed to investigate the effects of a high-cholesterol diet (HD) on body weight, lipid profile, inflammatory cytokines, plaque stability, and histopathological changes in Apolipoprotein E (ApoE)^-/- and wild-type (WT) mice, to clarify the underlying mechanisms of AS.

Methods: ApoE^-/- and wild-type mice were fed HD or normal diet (ND) for 4 weeks. Body weight was monitored weekly to assess the development of obesity. The serum levels of blood lipids and inflammatory factors were examined using the corresponding kits. The expression of plaque stability markers was confirmed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot. Besides, the structure and fat deposition of coronary artery tissues were assessed using hematoxylin and eosin (H&E), Masson trichrome, oil red O, Prussian blue, and immunohistochemical staining.

Results: Relative to the ND group, the body weight of mice notably increased in the HD group (p < 0.01). HD feeding elevated serum lipids and pro-inflammatory markers in ApoE^-/- and wild-type mice (p < 0.01). Expression of plaque instability markers was significantly upregulated in HD-fed groups (p < 0.05). Histological analysis revealed structural disorganization, increased lipid and iron deposition, and greater collagen accumulation in coronary tissues, particularly in the ApoE^-/- mice.

Conclusion: This study demonstrated that HD might accelerate AS by promoting obesity, dyslipidemia, inflammation, plaque instability, and vascular remodeling, especially in genetically susceptible ApoE^-/- mice. These results may provide new insights for AS prevention and therapy.