Adenosine A2A and A2B Receptors as Therapeutic Targets in Cardiovascular Diseases: Mechanistic Insights and Clinical Prospects

Abstract

Adenosine is a ubiquitous endogenous modulator that coordinates diverse physiological processes by binding to specific adenosine receptors (ARs). Among the four known AR subtypes, A2ARs and A2BRs are critical determinants of cardiovascular homeostasis. This narrative review comprehensively synthesizes current knowledge on the molecular mechanisms, signaling pathways, and cardiovascular effects of A2ARs and A2BRs, evaluating their therapeutic potential in the management of cardiovascular pathologies. Both receptor subtypes are widely distributed across cardiac and vascular tissues, where their activation engages multiple signaling cascades, including G protein-, PKC-, MAPK-, and PI3K/Akt-dependent cascades, to mediate beneficial effects in cardioprotection and vascular regulation. In ischemic heart disease, stimulation of A2ARs and A2BRs confers potent anti-ischemic, anti-inflammatory, and antifibrotic actions, collectively reducing infarct size and attenuating pathological myocardial fibrosis and remodeling. Additionally, A2ARs and A2BRs contribute to the regulation of vascular tone and function by promoting vasodilation, angiogenesis, and an improved endothelial function. Overall, this review underscores the multifaceted and critical roles of A2AR and A2BR in the cardiovascular system and highlights their emerging potential as promising therapeutic targets for cardiovascular diseases.