Adenosinergic cardioprotection: multiple receptors, multiple pathways.
Adenosine, formed primarily via hydrolysis of 5'-AMP, has been historically dubbed a "retaliatory" metabolite due to enhanced local release and beneficial actions during cellular/metabolic stress. From a cardiovascular perspective, evidence indicates the adenosinergic system is essential in mediation of intrinsic protection (e.g., pre- and postconditioning) and determining myocardial resistance to insult. Modulation of adenosine and its receptors thus remains a promising, though as yet not well-realized, approach to amelioration of injury in ischemic-reperfused myocardium. Adenosine exerts effects through A(1), A(2A), A(2B), and A(3) adenosine receptor subtypes (A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR), which are all expressed in myocardial and vascular cells, and couple to G proteins to trigger a range of responses (generally, but not always, beneficial). Adenosine can also enhance tolerance to injurious stimuli via receptor-independent metabolic effects. Given adenosines contribution to preconditioning, it is no surprise that postreceptor signaling typically mimics that associated with preconditioning. This involves activation/translocation of PKC, PI3 kinase, and MAPKs, with ultimate effects at the level of mitochondrial targets-the mitochondrial K(ATP) channel and/or the mitochondrial permeability transition pore (mPTP). Nonetheless, differences in cytoprotective signaling and actions of the different adenosine receptor subtypes have been recently revealed. Our understanding of adenosinergic cytoprotection continues to evolve, with roles for the A(2) subtypes emerging, together with evidence of essential receptor "cross-talk" in mediation of protection. This review focuses on current research into adenosine-mediated cardioprotection, highlighting recent findings which, together with a wealth of prior knowledge, may ultimately facilitate adenosinergic approaches to clinical cardiac protection.
Peart
Jason N
JN
Heart Foundation Research Center, Griffith University, PMB 50 Gold Coast Mail Center, QLD, 4217, Australia. j.peart@griffith.edu.au
Headrick
John P
JP
D000241:Adenosine / Q000378:metabolism*; D000368:Aged; D000375:Aging / Q000502:physiology; D000818:Animals; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D018047:Receptors, Purinergic P1; D000241:Adenosine