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

Original Research

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Authors: Teng B, Mustafa SJ

Published Date July 2011 Volume 2011:3 Pages 59 - 68

DOI: http://dx.doi.org/10.2147/JEP.S18945

Bunyen Teng, S Jamal Mustafa
Department of Physiology and Pharmacology and Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USA

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

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