Abstract
Background: Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A2A-adenosine receptor (A2A-AR).Methods and Results: To better understand its role in cardiac function, we generated and characterized mice (A2A-TG) which overexpress the human A2A-AR in cardiomyocytes. In isolated atrial preparations from A2A-TG but not from WT, CGS 21680, an A2A-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A2A-TG but not WT, CGS 21680 increased the cAMP content and the phosphorylation state of phospholamban and of the inhibitory subunit of troponin in A2A-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A2A-TG compared to WT. Protein expression of the α-subunit of the stimulatory G-protein was lower in A2A-TG than in WT but expression of the α-subunit of the inhibitory G-protein was higher in A2A-TG than in WT. While basal hemodynamic parameters like left intraventricular pressure and echocardiographic parameters like the systolic diameter of the interventricular septum were higher in A2A-TG than in WT, after β-adrenergic stimulation these differences disappeared. Interestingly, A2A-TG hearts sustained global ischemia better than WT.Conclusion: We have successfully generated transgenic mice with cardiospecific overexpression of a functional A2A-AR. This receptor is able to increase cardiac function per se and after receptor stimulation. It is speculated that this receptor may be useful to sustain contractility in failing human hearts and upon ischemia and reperfusion.
Highlights
Adenosine elicits multiple effects in the human body
Under the same experimental conditions used in samples from A2A-TG heart, no specific binding of A2A-adenosine receptors (AR) using the [3H]-labeled A2AAR-agonist CGS 21680 could be established in samples of the hearts from wild type (WT) littermates (Figure 1A)
We tentatively identified the localization of the receptor in A2A-TG to the vicinity of the sarcolemma (Figure 1B)
Summary
Adenosine elicits multiple effects in the human body. These include effects on cardiac function that have been studied for many years and some effects of adenosine including the downstream signaling mechanisms are similar to those of vagal stimulation. The negative chronotropic effect on the sinus node, the negative dromotropic effect on the AV-node, and the negative inotropic effect in atrial tissue of adenosine (Shryock and Belardinelli, 1997). Extracellular adenosine acts on A1-, A2-, and A3-adenosine receptors (AR). A1-AR inhibits and A2-AR stimulates adenylyl cyclase activities (Olsson and Pearson, 1990). Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A2A-adenosine receptor (A2A-AR)
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