Cardiovascular diseases (CVDs) are the prominent cause of death globally, taking an estimated 17.9 million lives each year [1]. CVDs are a group of disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other conditions [1].

A recent revival of cardiovascular drug development has introduced new pharmacological strategies to the market, with numerous promising therapies in various stages of pre-clinical and clinical development [2]. In this regard, extracellular adenosine is involved in the pathogenesis of several CVDs, including hypertension [3], heart failure (HF) [4], atherosclerosis [5], ischemic injury [6], cardiomyopathies (CMs) [7], and myocardial infarction (MI) [8], thus representing an intriguing target to design novel pharmacological tools aimed at managing patients with cardiovascular disorders. In particular, adenosine is a ubiquitous nucleoside mainly generated as a result of sequential dephosphorylation of ATP, ADP, and AMP in the extracellular space [9]. Adenosine or its precursors ATP, ADP, and AMP are massively released under adverse conditions, including hypoxia, ischemia, and inflammation [9]. Once in the extracellular space, adenosine modulates physiological processes involving the heart and the cardiovascular system, through the activation of four G-coupled membrane receptors, named A1, A2A, A2B, and A3 [10]. In particular, adenosine strongly impacts on the physiological regulation of cardiovascular activity, such as heart rate, vasomodulation, and blood pressure regulation, mainly through the activation of its receptors, widely expressed in this context [10].

Of note, a rising body of evidence indicates that an abnormal immuno-inflammatory activation is critically involved in many CVDs [11]. Indeed, it has been widely demonstrated that atherosclerosis is predominantly a chronic inflammatory disease of the arterial wall indicating that an alteration of the immune/inflammatory pathways may be the leading mechanisms in a number of CVDs [11]. Adenosine, which accumulates in the extracellular space at sites of tissue damage, is involved in the modulation of immune responses and restraining inflammatory tissue damage [12, 13, 14, 15, 16∗, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26]. A number of studies indicate that extracellular adenosine is a “retaliatory metabolite,” meaning that it is generated as a result of cellular injury or stress, and that through interacting with adenosine receptors, it finely modulates the immune/inflammatory cell activity in order to shield tissues from injury and stress [12,27,28]. For this reason, the pharmacological modulation of the adenosine system may represent an useful target for the management of CVDs, acting either directly on the cardiovascular compartment by modulating its activity or on the immune cell populations involved in the onset and development on cardiovascular disorders.

Based on these premises, the present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of CVDs. Particular attention has been focused on current scientific evidence about the pharmacological ligands acting on adenosine pathway as useful tools to manage CVDs.