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1 Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA; Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia, USA
2 Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
3 School of Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
4 Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia, USA; Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, USA
* To whom correspondence should be addressed. E-mail: arl2b{at}virginia.edu.
Activation of A1 adenosine receptors (A1AR) may be a crucial step in protection against myocardial ischemia/reperfusion (I/R) injury, however the use of pharmacologic A1AR antagonists to inhibit myocardial protection has yielded inconclusive results. In the current study we have used mice with genetically modified A1AR expression to define the role of A1AR in intrinsic protection and ischemic preconditioning (IPC) against I/R injury. Mice with normal (WT), deleted (A1KO-/-), single copy (A1KO+/-) and increased (A1TG) cardiac A1AR expression underwent 45 min LAD occlusion followed by 60 min reperfusion. Subsets of each group were preconditioned with short durations of ischemia (3 cycles of 5 min occlusion, 5 min reperfusion) prior to index ischemia. Infarct size (IF) in WT, A1KO+/- and A1KO-/- mice was 58±3, 60±4 and 61±2 (% risk region) respectively, and was less in A1TG mice (39±4, p<0.05). A strong correlation was observed between A1AR expression level and response to IPC. IF was significantly reduced by IPC in WT mice (35±3, p<0.05 vs. WT), A1KO+/-+IPC (48±4, p<0.05 vs. A1KO+/-), and A1TG+IPC mice (24±2, p<0.05 v. A1TG). However, IPC did not decrease IF in A1KO-/-+IPC mice (63±2). In addition, A1KO-/- hearts subjected to global I/R injury demonstrated diminished recovery of developed pressure and diastolic function as compared to wild-type controls. These findings demonstrate that A1AR are critical to protection from myocardial ischemia-reperfusion injury and that cardioprotection with ischemic preconditioning is relative to the level of A1AR gene expression.
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