Adenosine A 3 Receptor and Cardioprotection

Abstract

Ischemic injury to the myocardium is a leading cause of morbidity and mortality around the globe.1 It is worth remembering, however, that this insult to the heart emerged only in the last few centuries, an instant in time from an evolutionary perspective. Thus, any cardioprotective responses to ischemic injury undoubtedly evolved for an entirely different purpose. Beyond pure academic interest, however, there is a profound clinical need to identify new means of protecting the myocardium from disease-related stress. Among the strategies in development is a concerted effort to understand and enhance the body’s innate mechanisms of cardioprotection. Article p 1713 Among these cardioprotective mechanisms is one mediated by the molecule adenosine. This purine nucleoside, derived largely as a metabolite of 5′-AMP, coordinates organ metabolism and blood supply and modulates immune responses. Under conditions of cellular/metabolic stress, activation of the adenosinergic system has beneficial effects, and in heart, adenosine has well-established functions to mitigate myocardial damage from ischemia-reperfusion injury.2 For this reason, there is great interest in adenosinergic signaling as a means of treating ischemic heart disease. However, the biology of adenosinergic signaling in several organ systems has proven complex, manifesting context-dependent pro- and anti-survival actions. A number of mechanisms have been invoked to explain the cardioprotective actions of adenosine. These include preservation of ATP levels, stimulation of glycolysis, and limitation of oxygen demand. Some of these events are mediated by alterations in protein kinase C, phosphoinositide-3 kinase, and mitogen-activated protein kinase signaling pathways. To cite 1 example, A1 adenosine receptor antagonism prevents ischemia-induced sensitization of adenylyl cyclase via a protein kinase C–mediated pathway.3 However, there is considerable disagreement in the literature, possibly resulting from the fact that several commonly used signaling inhibitors, including inhibitors of protein kinase C, significantly limit agonism of adenosine receptors.4 Adenosine …