P2X7 Receptor Antagonist A740003 Mitigates Cardiac Senescence by Inhibiting Inflammaging Through the NF-κB Pathway

Background: Inflammaging is a hallmark of cardiac aging that can develop through the NF-κB pathway. Purinergic P2X7 receptors (P2X7Rs) mediate inflammation in cardiovascular diseases. However, the role of P2X7Rs in cardiac inflammaging remains unclear. This research aims to explore the association between P2X7Rs and cardiac inflammaging and whether pharmacological inhibition of P2X7Rs (A740003) can alleviate aging-related cardiac inflammation by regulating the NF-κB pathway in an animal model of cardiac aging. Methods: Wistar albino rats were subjected to intraperitoneal administration of D-galactose (200 mg/kg/day) for 10 weeks to induce cardiac aging. Four groups of eight rats each were divided into: normal control (saline for 10 weeks); aging control (D-galactose + saline from weeks 8-10); aging + vehicle (D-galactose + vehicle from weeks 8-10); and aging + A740003 (D-galactose + A740003 (19 mg/kg/day) from weeks 8-10). Heart tissues were then histologically examined and cardiac cellular senescence markers, including SA-β-Gal activity, p16^Ink4a and p21^Cip/Waf expression, and pro-inflammatory senescence-associated secretory phenotype (SASP) factors, were assessed. Expression of P2X7R, NF-κBp105, and NF-κBp65 was detected. Results: Treatment with A740003 reduced cellular senescence markers and pro-inflammatory SASP factors. The expression of P2X7R, NF-κBp105, and NF-κBp65 was significantly increased in cardiac tissues of the aging group, whereas the expression of IκB was decreased. A740003 treatment decreased the levels of P2X7R, NF-κBp105 and NF-κBp65. Conclusions: Data indicate that A740003 alleviates cardiac inflammaging through inhibition of the P2X7R-mediated NF-κB mechanism. Therefore, the P2X7R-mediated NF-κB pathway may provide a novel strategy for mitigating age-related inflammation and preventing age-related cardiovascular diseases.