Oxidative stress and atherosclerosis: from LDL oxidation and foam cell formation to plaque instability – three decades of evidence and remaining therapeutic challenges

Atherosclerosis remains the leading cause of cardiovascular morbidity and mortality worldwide. Over the past three decades, compelling evidence has established oxidative stress as a central pathogenic mechanism in atherogenesis, driving low-density lipoprotein (LDL) oxidation, foam cell formation, vascular inflammation, and ultimately plaque instability. This comprehensive review synthesizes current knowledge on the multifaceted role of reactive oxygen species (ROS) and oxidative stress in atherosclerosis progression. We examine the molecular mechanisms underlying LDL oxidation and its subsequent uptake by macrophage scavenger receptors, leading to foam cell formation. The contribution of oxidative stress to plaque vulnerability through matrix metalloproteinase activation, neovascularization, and necrotic core expansion is critically analyzed. Furthermore, we discuss the translation of this knowledge into therapeutic strategies, including the disappointing outcomes of antioxidant vitamin trials and the emergence of novel targeted approaches such as mitochondria-specific antioxidants and NADPH oxidase inhibitors. Despite significant advances in understanding the pathophysiology, effective anti-atherosclerotic therapies targeting oxidative stress remain elusive. This review identifies persistent gaps in knowledge and outlines future directions for research and therapeutic development. The complex interplay between oxidative stress, inflammation, and lipid metabolism continues to present both challenges and opportunities for cardiovascular medicine.