Phenotyping of Mice with Heart Specific Overexpression of A2A-Adenosine Receptors: Evidence for Cardioprotective Effects of A2A-Adenosine Receptors

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

Evidence for Arrhythmogenic Effects of A-Adenosine Receptors.

Adenosine can be released from the heart and may stimulate four different cardiac adenosine receptors. A receptor subtype that couples to the generation of cyclic adenosine monophosphate (cAMP) is the A-adenosine receptor (A-AR). To better understand its role in cardiac function, we studied mechanical and electrophysiological effects in transgenic mice that overexpress the human A-AR in cardiomyocytes (A-TG). We used isolated preparations from the left atrium, the right atrium, isolated perfused hearts with surface electrocardiogram (ECG) recording, and surface body ECG recordings of living mice. The hypothesized arrhythmogenic effects of transgenicity per se and A-AR stimulation were studied. We noted an increase in the incidence of supraventricular and ventricular arrhythmias under these conditions in A-TG. Moreover, we noted that the A-AR agonist CGS 21680 exerted positive inotropic effect in isolated human electrically driven (1 Hz) right atrial trabeculae carneae. We conclude that A-ARs are functional not only in A-TG but also in isolated human atrial preparations. A-ARs in A-TG per se and their stimulation can lead to cardiac arrhythmias not only in isolated cardiac preparations from A-TG but also in living A-TG