Background: Atherosclerosis is a lipoprotein-driven disease that leads to plaque formation at specific sites of the arterial tree through intimal inflammation, fibrosis, necrosis, and calcification. Sometimes such plaques may suddenly cause life-threatening coronary thrombosis clinically described as acute coronary syndrome. Hypothesis: An atherosclerotic rabbit model, with a lipoprotein metabolism similar to the human patient, have been proposed to explore the mechanisms leading to plaque instability. We expect to identify an unambiguous alarmin expression pattern, associated to specific atherogenic signalling pathways that may explain the residual risk of cardiovascular-related events and associated mortality. Aim: The project will explore the plaque instability and the early signs of risks and/or protective factors in coronary disease by using an experimental design comprising both the classical pharmacology (statin administration) and the newest generation of molecular biology approaches (RNA silencing or biological active agents such as PCSK9 antibodies). In preliminary studies the hypercholesterolemic food concentration and treatment to be used was evaluated. Methodology: Adult male New Zeeland White rabbits (16 weeks-old) were randomly split into 5 groups: two animals were fed a diet containing either 0.5% or 1% high cholesterol diet and three animals were fed a standard diet together with inhibition of PCSK9 for 4 weeks. The inhibition of PCSK9 were obtained either with siRNA (molecule I or II) or using monoclonal antibodies against PCSK9 (Evolocumab, Repatha, AMGEN). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL), triglyceride levels were measured by using Dialab kits. Levels of PCSK9 protein in plasma samples were detected by ELISA kit. The presence and the quantification of atherosclerotic lesions were assessed by Oil Red O and hematoxylin and eosin staining. Results: The hypercholesterolemic diet induces a significant increase in lipid parameters in the plasma. In the present study, we found that irrespective of the cholesterol concentration diet the atherosclerotic plaques had more macrophage accumulation in the aortic lesion area and higher expression of α-smooth muscle actin and CD31 endothelial specific antigen were detected than in the animals fed a standard diet. The administration of anti PCSK9 antibody showed a decrease of the plasma PCSK9 protein in the treated animals. Conclusion: The preliminary results suggest that hypercholesterolemic diet induces atherosclerotic plaque progression in rabbit model and for more advanced lesions, the 0.5% cholesterol diet will be extended to 12 weeks. The inhibition with anti PCSK9 demonstrated to be functioning in the decreasing of LDL plasma and could be successfully used in the proposed study. Acknowledgments: The work was supported by the Romanian Academy and Ministry of Research and Innovation grant UEFISCI no. 41/2018.