Vascular and Hypertension Research Unit, Lady Davis Institute for Medical Research (B.G.S., P.P., E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Department of Medicine (E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):186-199. doi: 10.1161/ATVBAHA.120.315116. Epub 2020 Oct 1.
Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.
慢性低度炎症是多种疾病（包括心血管疾病）发展的原因之一。针对心血管疾病中的炎症的适当策略还处于起步阶段，仍然是一个非常有意义的研究领域。嘌呤能受体 P2X7 是一种广泛表达的受体，主要介导炎症和细胞死亡。P2X7 是一种配体门控阳离子通道，在细胞外 ATP 浓度升高时被激活，触发 NLRP3（核寡聚结构域样受体家族含pyrin 结构域 3）炎性小体的组装和激活，随后释放促炎细胞因子 IL（白细胞介素）-1β 和 IL-18。P2X7 激活增加以及 IL-1β 和 IL-18 浓度升高与许多心血管疾病的发展有关，包括高血压、动脉粥样硬化、缺血/再灌注损伤和心力衰竭。P2X7 受体 KO（敲除）小鼠表现出炎症反应的显著减弱，这与疾病严重程度的降低相对应。在高血压动物模型中，P2X7 拮抗剂可减轻血压升高，在动脉粥样硬化动物模型中可减缓疾病进展。IL-1β 和 IL-18 抑制剂在临床试验中显示出疗效，可减少主要不良心脏事件，包括心肌梗死和心力衰竭。由于有几种具有已证实安全裕度的 P2X7 拮抗剂，因此 P2X7 拮抗剂可能是治疗心血管疾病的潜在手段。
