心血管疾病(CVDs),尤其是心力衰竭,是全球早期死亡率的主要贡献者。心力衰竭是一个严重的公共卫生问题,患者长期结局持续不佳,总体预后不理想。传统上,心力衰竭的治疗方法主要集中在降低血压;然而,开发更有效的针对血液动力学参数的疗法面临挑战,包括耐受性和安全风险,这可能会限制其临床有效性。腺苷已经成为心血管疾病的关键中介,作为通过ATP代谢在细胞应激期间产生的报复性代谢产物,并作为调节各种生理过程的信号分子。腺苷通过与心脏细胞中表达的不同腺苷受体(AR)亚型相互作用而发挥功能,包括A1AR,A2AAR,A2BAR,A3AR除了A1AR,A3AR在心血管系统中具有多方面的作用,因为它的激活有助于减少各种病理状态下对心脏的损害,尤其是缺血性心脏病,心力衰竭,和高血压,尽管与其他AR亚型相比,其作用没有得到很好的证明。对A3AR信号传导的研究集中在通过各种途径识别参与CVD的复杂分子机制。包括Gi或Gq蛋白依赖性信号,ATP敏感性钾通道,MAPK,和G蛋白无关的信号。几种A3AR特异性激动剂,比如piclidenoson和namodenoson,在不同的心脏病动物模型中,在缺血期间发挥心脏保护作用。因此,调节A3AR作为一种潜在的治疗方法,激发了人们对开发靶向A3AR的化合物作为心脏病潜在治疗方法的极大兴趣。
Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including A1AR, A2AAR, A2BAR, and A3AR. In addition to A1AR, A3AR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on A3AR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including Gi or Gq protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several A3AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A3ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A3ARs as potential treatments for heart diseases.