Adenosine receptor subtypes and the heart failure phenotype: translating lessons from mice to man

Adenosine plays an important role in the pathophysiology of heart failure and in myocardial protection during ischemia and reperfusion. The action of adenosine in the heart is mediated by four G-protein-coupled receptors: A(1)-AR and A(3)-AR, which act via Gα(1), and A(2A)-AR and A(2B)-AR, which act via Gα(s). Understanding of cellular signaling pathways triggered by adenosine has been complicated by the availability of only partially specific adenosine agonists/antagonists. Adenosine signaling appears to be at times redundant in receptor function, and cellular signaling pathways for adenosine are multiple, parallel, and interrelated. Data obtained about the specific role of individual adenosine receptors, through the genetic modulation of receptors in murine hearts have provided important information about the role of adenosine receptors in the heart. Here we review existing data and present new results that clarify the function of individual adenosine receptors in the heart and their role in the development of left ventricular dysfunction, and about the downstream signaling systems that are modified by adenosine receptor activation.