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1 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
2 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA
3 Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven, Gasthuisberg, Leuven, Belgium
4 Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: bf4g{at}virginia.edu.
Background - Following myocardial infarction (MI), contractile dysfunction develops not only in the infarct zone, but also in non-infarcted regions of the left ventricle (LV) remote from the infarct zone. Inflammatory activation secondary to MI stimulates iNOS induction with excess production of nitric oxide. We hypothesized that the anti-inflammatory effects of selective A2A-adenosine receptor (A2AAR) stimulation would suppress inflammation and preserve cardiac function in the remote zone early after MI. Methods and Results - A total of fifty-three mice underwent 60 minutes of coronary occlusion followed by 24 hours of reperfusion. The A2AAR agonist (ATL146e, 2.4 µg/kg) was administered intraperitoneally 1, 3 and 6 hours post-reperfusion. Due to the 1 hour delay in treatment after MI, ATL146e had no effect on infarct size as demonstrated by contrast-enhanced cardiac MRI (n=18) performed 24 hours post-MI. ATL146e did, however, preserve global cardiac function at that time by limiting contractile dysfunction in remote regions (LV wall thickening: 51±4% in treated (n=9) vs. 29±3% in non-treated groups (n=9), P<0.01). RT-PCR, immunohistochemistry and Western blot analysis indicated that iNOS mRNA and protein expression were significantly reduced by ATL146e treatment in both infarcted and non-infarcted zones. Similarly, elevations in plasma nitrate/nitrite following MI were substantially blunted by ATL146e (P<0.01). Finally, treatment with ATL146e reduced NF-
B activation in the myocardium by over 50%; not only in the infarct zone, but also in non-infarcted regions (P<0.05). Conclusion - A2AAR stimulation after MI suppresses inflammatory activation and preserves cardiac function, suggesting the potential utility of A2AAR agonists against acute heart failure in the immediate post-MI period.
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