Extracellular ATP Signaling as a Proposed Mechanistic Link to Cellular Senescence in Cardiovascular Diseases

Cellular senescence represents a critical pathological process involved in the progression of cardiovascular diseases (CVDs). Senescent endothelial cells, cardiomyocytes, vascular smooth muscle cells (VSMCs), and immune cells can promote inflammatory responses, oxidative stress, extracellular matrix (ECM) degradation, and fibrotic remodeling through the senescence-associated secretory phenotype (SASP). Beyond its fundamental role in intracellular energy metabolism, adenosine triphosphate (ATP) can also be released into the extracellular environment under conditions such as ischemia-reperfusion injury (IRI), mechanical stress, inflammatory stimulation, and cellular damage, where it participates in cellular stress responses through P2X/P2Y purinergic receptors. This article proposes the hypothesis that ATP-induced cellular senescence (AICS) contributes to CVD progression, suggesting that sustained or abnormally enhanced extracellular ATP signaling may promote cardiovascular cell senescence through disruption of Ca2⁺ homeostasis, mitochondrial reactive oxygen species (ROS) accumulation, activation of DNA damage response (DDR) pathways, NLRP3 inflammasome activation, enhanced NF-κB signaling, and persistent maintenance of the SASP. However, ATP signaling is highly dependent on its concentration, exposure duration, receptor subtype, and cellular context, and therefore cannot be simply regarded as a pro-senescence signal. Further studies using CVD-specific models and human pathological samples are required to establish the causal relationship among ATP/P2 receptor activation, cellular senescence burden, and disease progression.