Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of LDL, primarily composed of Apolipoprotein B (ApoB). Various strategies have been proposed for the treatment of atherosclerosis, mainly focused on reducing LDL levels, such as statins. However, these approaches are often insufficient to prevent the risk of thrombosis. It is known that post-translational protein modifications (PTMs) regulate the activity of numerous cellular pathways, and some evidence relate them to atherosclerosis. However, their involvement in the development of atherosclerosis and their potential as therapeutic targets have not yet been explored form an unbiased, high-throughput perspective. To study the role of PTM and its association with plaque activity, we analysed tissue and plasma samples from pig and mouse atherosclerotic regression models, as well as patients with subclinical atherosclerosis, totaling 1080 samples. We conducted a comprehensive and unbiased analysis of PTMs using an "Open-Search" strategy using Comet-PTM and a novel integrative quantitative workflow, both developed in our laboratory. We have detected numerous modifications that are associated with decreased plaque activity. Since Smooth Muscle Cells (SMCs) are the principal producer of extracellular matrix during atherosclerotic plaque development and are responsible for plaque stability, we also performed a PTM-based analysis focused on these cells. Specifically, we analyzed an extracellular matrix preparation from primary cultured SMCs using a mouse regression model (n=10). We have also performed a preliminary study using Single Cell Proteomics of mouse aortic SMCs from a mouse regression model. Preliminary results revealed that several PTMs previously observed at the tissue and plasma level are present in SMCs and their extracellular matrix, reflecting the relevance of PTMs in SMCs during atherosclerosis. Our results suggest the existence of PTMs associated with atherosclerosis progression and regression, supporting the idea that modifications could have unprecedent implications in vascular remodelling, and open the way to the study of their mechanistic implications.