Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis.

Atherosclerosis features chronic inflammation and lipid accumulation; vascular smooth muscle cells (VSMCs) contribute by proliferating and becoming foam cells via oxidized LDL (ox-LDL) uptake through lectin-like ox-LDL receptor-1 (LOX-1). To test whether ginsenoside Rb1 limits neointima formation and atherosclerosis by inhibiting VSMC proliferation and foam formation via c-JUN/AP-1-dependent regulation of LOX-1, with autophagy as a supportive mechanism. In vivo carotid ligation models (complete in C57BL/6 J; partial in ApoE-/-) with perivascular Rb1 in F-127 hydrogel, plus in vitro analyses in A7R5 VSMCs. Lesion burden was quantified histologically. VSMC proliferation (EdU, cell-cycle proteins), lipid accumulation (Oil Red O, BODIPY), intracellular cholesterol, and Dil-ox-LDL uptake were measured. Network pharmacology/docking nominated targets; biotin-Rb1 pull-down validated binding. c-JUN phosphorylation/AP-1 activity, LOX-1 expression, and autophagy markers (LC3-II, p62) were assessed; AP-1 was inhibited with T5224. Rb1 reduced ligation-induced neointima in C57BL/6 J mice and decreased plaque size and lipid content in ApoE-/- carotids. In VSMCs, Rb1 suppressed proliferation, lowered ox-LDL uptake and total cholesterol, downregulated LOX-1. Network analyses identified JUN among the top Rb1 targets; docking predicted binding and pull-down confirmed direct interaction with c-JUN (and PTGS2). Rb1 decreased c-JUN phosphorylation and AP-1 activity; AP-1 blockade with T5224 recapitulated reductions in LOX-1 and ox-LDL uptake. Rb1 increased LC3-II and decreased p62, consistent with enhanced autophagy. Rb1 mitigates atherosclerosis by inhibiting VSMC proliferation and foam formation through suppression of c-JUN/AP-1-mediated LOX-1 transcription and activation of autophagy. These actions support Rb1 as a promising phytotherapeutic for plaque attenuation and stabilization.

Apurinic/apyrimidinic endonuclease 1 (APEX1) serves as a potent regulatory factor in innate immunity, exhibiting both redox and endonuclease activities. Its redox function enables the regulation of transcription factors such as NF-κB or STAT3, whereas its endonuclease activity recognizes apurinic/apyrimidinic (AP) sites in damaged DNA lesions during base excision repair (BER) and double-stranded DNA repair, thereby I confirm.anti-inflammatory, antioxidative stress and antiapoptotic effects. APEX1 is expressed in a variety of cell types that constitute the cardiovascular system, including cardiomyocytes, endothelial cells, smooth muscle cells, and immune cells. Emerging genetic and experimental evidence points towards the functional roles of APEX1 in the pathophysiology of cardiovascular diseases, including neointimal formation and atherosclerosis. This review aims to present comprehensive coverage of the up-to-date literature concerning the molecular and cellular functions of APEX1, with a particular focus on how APEX1 contributes to the (dys)functions of different cell types during the pathogenesis of cardiovascular diseases. Furthermore, we underscore the potential of APEX1 as a therapeutic target for the treatment of cardiovascular diseases.