A_2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE–knockout mice

Abstract

Adenosine-induced coronary vasodilation is predominantly A_2A adenosine receptor (AR)-mediated, whereas A₁ AR is known to negatively modulate the coronary flow (CF). However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not well understood. Using hyperlipidemic/atherosclerotic apolipoprotein E (APOE)–knockout mice, CF responses to nonspecific adenosine agonist (5′-N-ethylcarboxamide adenosine, NECA) and specific adenosine agonists (2-chloro-N6-cyclopentyl-adenosine [CCPA, A₁ AR-specific] and CGS-21680, A_2A AR-specific) were assessed using isolated Langendorff hearts. Western blot analysis was performed in the aorta from APOE and their wild-type (WT) control (C57BL/6J). Baseline CF (expressed as mL/min/g heart weight) was not different among WT (13.23 ± 3.58), APOE (13.22 ± 2.78), and APOE on high-fat diet (HFD) for 12 weeks (APOE-HFD, 12.37 ± 4.76). Concentration response curves induced by CGS-21680 were significantly shifted to the left in APOE and APOE-HFD when compared with WT. CCPA induced an increase in CF only at 10⁻⁶ M in all groups and the effect was reversed by the addition of a selective A_2A AR antagonist, SCH-58261 (10⁻⁶ M), and a significant decrease in CF from baseline was observed. Western blot analysis showed a significant upregulation of A_2A AR in the aorta from APOE and APOE-HFD. This study provides the first evidence that CF responses to A_2A AR stimulation were upregulated in hyperlipidemic/atherosclerotic animals. The speculation is that the use of A_2A AR-specific agonist for myocardial perfusion imaging (such as regadenoson) could overestimate the coronary reserve in coronary artery disease patients.

Keywords:

• hyperlipidemia
• atherosclerosis
• apolipoprotein E–knockout mice
• coronary flow regulation
• A_2A adenosine receptor

Acknowledgments

The authors would like to thank Kevin P Roush for his technical assistance. Supported by Research Development Grant from West Virginia University and NIH HL 027339 and HL 094447.

Disclosure

The authors report no conflicts of interest in this work.