Boknik Peter, Drzewiecki Katharina, Eskandar John, Gergs Ulrich, Grote-Wessels Stephanie, Fabritz Larissa, Kirchhof Paulus, Müller Frank U, Stümpel Frank, Schmitz Wilhelm, Zimmermann Norbert, Kirchhefer Uwe, Neumann Joachim
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Münster, Germany.
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
Front Pharmacol. 2018 Jan 22;9:13. doi: 10.3389/fphar.2018.00013. eCollection 2018.
Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A-adenosine receptor (A-AR). To better understand its role in cardiac function, we generated and characterized mice (A-TG) which overexpress the human A-AR in cardiomyocytes. In isolated atrial preparations from A-TG but not from WT, CGS 21680, an A-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A-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-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A-TG compared to WT. Protein expression of the α-subunit of the stimulatory G-protein was lower in A-TG than in WT but expression of the α-subunit of the inhibitory G-protein was higher in A-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-TG than in WT, after β-adrenergic stimulation these differences disappeared. Interestingly, A-TG hearts sustained global ischemia better than WT. We have successfully generated transgenic mice with cardiospecific overexpression of a functional A-AR. This receptor is able to increase cardiac function 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.
腺苷可在心脏中产生，并作用于心脏腺苷受体。其中一种受体是A1 - 腺苷受体（A1 - AR）。为了更好地了解其在心脏功能中的作用，我们构建并鉴定了在心肌细胞中过表达人A1 - AR的小鼠（A1 - TG）。在来自A1 - TG而非野生型（WT）的离体心房标本中，A1 - AR激动剂CGS 21680发挥了正性变力和变时作用。在来自A1 - TG而非WT的心室标本中，CGS 21680增加了A1 - TG而非WT中的环磷酸腺苷（cAMP）含量以及受磷蛋白和肌钙蛋白抑制亚基的磷酸化状态。与WT相比，A1 - TG中受磷蛋白、肌浆网钙ATP酶（SERCA）、三联蛋白和连接蛋白的蛋白表达没有变化。A1 - TG中刺激性G蛋白α亚基的蛋白表达低于WT，但抑制性G蛋白α亚基的表达在A1 - TG中高于WT。虽然A1 - TG中的基础血流动力学参数如左心室内压和超声心动图参数如室间隔收缩直径高于WT，但在β - 肾上腺素能刺激后这些差异消失。有趣的是，A1 - TG心脏比WT更好地耐受整体缺血。我们成功构建了具有心脏特异性过表达功能性A1 - AR的转基因小鼠。该受体能够在受体刺激后增强心脏功能。据推测，该受体可能有助于维持衰竭的人类心脏以及缺血和再灌注时的收缩力。
