A2A Adenosine Receptor‐Mediated Coronary Flow Increase Is Enhanced in Hyperlipidemic Mice

Abstract

Adenosine-induced coronary vasodilation is predominantly A2A AR-mediated; while A1 AR is known to negatively modulate vasodilation. However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not clear. Using hyperlipidemic/atherosclerotic apolipoprotein E knockout mice (APOE-KO) model, coronary flow responses to non-specific (NECA) and specific adenosine agonists (CCPA, A1 AR specific, and CGS-21680, A2A AR specific) were assessed by Langendorff experiments. Western blots for A1 AR and A2A AR were performed in the aorta from APOE-KO and their wild type control (C57BL/6J). All mice were 20–23 weeks old. Baseline CF (expressed as ml/min/gram heart weight) was not different between C57BL/6J (12.52±4), APOE-KO (11.95±1.71), and APOE-KO on high fat diet for 12 weeks (APOE-KO-HFD, 12.18±4.75). NECA- and CGS-21680-induced increases in CF were both shifted to the left in APOE-KO and APOE-KO-HFD when compared to C57BL/6 (Figs. 1 and 2). CCPA also induced increase in CF at 10−6M in all groups and the effect was reversed by the addition of selective A2A AR antagonist, SCh-58261 (SCh, Fig. 3), and a significant decrease in CF from baseline was observed. Western blot analysis also demonstrated significant up-regulation of A2A AR in the aorta from APOE-KO and APOE-KO-HFD (Fig. 4). Therefore, CF responses to A2A AR stimulation were up-regulated in hyperlipidemic/atherosclerotic animals. Based on this, we can speculate that the use of adenosine or A2A AR specific agonist (such as Lexican® from CVTherapeutics) may be over estimating the coronary reserve in hyperlipidemic/atherosclerotic patients. Supported by NIH HL 027339 and HL094447. Figure 1Open in figure viewerPowerPoint Figure 2Open in figure viewerPowerPoint Figure 3Open in figure viewerPowerPoint Figure 4Open in figure viewerPowerPoint