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, A_2ARs and A_2BRs are critical determinants of cardiovascular homeostasis. This narrative review comprehensively synthesizes current knowledge on the molecular mechanisms, signaling pathways, and cardiovascular effects of A_2ARs and A_2BRs, 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 A_2ARs and A_2BRs confers potent anti-ischemic, anti-inflammatory, and antifibrotic actions, collectively reducing infarct size and attenuating pathological myocardial fibrosis and remodeling. Additionally, A_2ARs and A_2BRs 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 A_2AR and A_2BR in the cardiovascular system and highlights their emerging potential as promising therapeutic targets for cardiovascular diseases.