Phenotyping of Mice with Heart Specific Overexpression of A(2A)-Adenosine Receptors: Evidence for Cardioprotective Effects of A(2A)-Adenosine Receptors

作者：Boknik Peter; Drzewiecki Katharina; Eskandar John; Gergs Ulrich^*; Grote Wessels Stephanie; Fabritz Larissa; Kirchhof Paulus; Mueller Frank U; Stuempel Frank; Schmitz Wilhelm; Zimmermann Norbert; Kirchhefer Uwe; Neumann Joachim^*

来源：Frontiers in Pharmacology, 2018, 9: 13.

DOI：10.3389/fphar.2018.00013

• A(2A)-adenosine receptor
• contractility
• ischemia
• reperfusion
• protein phosphorylation

Background: Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A(2A)-adenosine receptor (A(2A)-AR).
Methods and Results: To better understand its role in cardiac function, we generated and characterized mice (A(2A)-TG) which overexpress the human A(2A)-AR in cardiomyocytes. In isolated atrial preparations from A(2A)-TG but not from WT, CGS 21680, an A(2A)-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A(2A)-TG but not WT, CGS 21680 increased the cAMP content and the phosphorylation state of phospholamban and of the inhibitory subunit of troponin in A(2A)-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A(2A)-TG compared to WT. Protein expression of the alpha-subunit of the stimulatory G-protein was lower in A(2A)-TG than in WT but expression of the alpha-subunit of the inhibitory G-protein was higher in A(2A)-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 A(2A)-TG than in WT, after beta-adrenergic stimulation these differences disappeared. Interestingly, A(2A)-TG hearts sustained global ischemia better than WT.
Conclusion: We have successfully generated transgenic mice with cardiospecific overexpression of a functional A(2A)-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.

• 出版日期2018-1-22