Adenosine and its receptors in the heart: Regulation, retaliation and adaptation

Abstract

The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A(1), A(2A), A(2B), and A(3)ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity (e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…This profile stems from a handful of changes spanning pathways (i.e. Gnb1, Nfat2c, Acta1, Prkar2b, Map3k2 and Pde3b), supporting effects of A 2A R activity on G protein and cAMP/PKA signalling downstream of the receptor [5,8,60]. Deletion of the A 2A R has been shown to reduce cAMP and PKA activation in other cell types [61], consistent with impacts of KO here ( Table 3).…”

“…In this regard, adenosine 2A receptors (A 2A Rs) may fulfil a broadly suppressive role to limit inflammatory injury in multiple tissues [3][4][5][6] and enhance myocardial resistance to ischaemic/hypoxic insult, presenting a potentially useful therapeutic target [3,7]. In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10]. Inflammatory modulation contributes to this latter cardioprotection [9][10][11], together with the regulation of myocyte kinase signals to limit oxidative stress, mitochondrial dysfunction and cell death [12][13][14].…”

The Effect of ACP1-ADA1Genetic Interaction on Human Life Span

“…events (Cohen and Downey 2008;Headrick et al 2011;Latini and Pedata 2001;Mubagwa and Flameng 2001;Peaeson et al 2003;Pedata et al 2007). …”

“…Transient activation of adenosine receptors protects against damage following hypoxic or ischemic events in brain and in other excitable tissues such as heart. Variation in energy states, cardiac stress or other stimuli induce the release of adenosine which by its receptors can lead to a more efficient balance between energy utilization and energy supply, also protecting cardiac cells under extreme stress conditions (Headrick et al 2011). …”

Thyroid hormones decrease the affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a competitive antagonist, for the guinea pig atrial A1 adenosine receptor

“…Some of these actions affect the purinergic system of the heart. In the myocardium, the A 1 and A 3 adenosine receptors are primarily involved (Headrick et al , 2011Headrick and Lasley 2009).…”