Role of A<inf>1</inf> adenosine receptor in cardiovascular diseases: Bridging molecular mechanisms with therapeutic opportunities

Abstract

Adenosine serves as a critical homeostatic regulator, exerting influence over physiological and pathological conditions in the cardiovascular system. During cellular stress, increased extracellular adenosine levels have been implicated in conferring cardioprotective effects through the activation of adenosine receptors with the A1 adenosine receptor subtype showing the highest expression in the heart. A1 adenosine receptor stimulation inhibits adenylyl cyclase activity via heterotrimeric Gi proteins, leading to the activation of distinct downstream effectors involved in cardiovascular homeostasis. While the comprehensive characterization of the pharmacological functions and intracellular signaling pathways associated with the A1 adenosine receptor subtype is still ongoing, this receptor is widely recognized as a crucial pharmacological target for the treatment of various states of cardiovascular diseases (CVDs). In this review, we focus on elucidating signal transduction of A1 adenosine receptor, particularly Gi protein-dependent and -independent pathways, and their relevance to cardiovascular protective effects as well as pathological consequences during cellular and tissue stresses in the cardiovascular system. Additionally, we provide comprehensive updates and detailed insights into a range of A1 adenosine receptor agonists and antagonists, detailing their development and evaluation through preclinical and clinical studies with a specific focus on their potential for the management of CVDs, especially heart diseases.