Stimulation of A2A-adenosine receptors after myocardial infarction suppresses inflammatory activation and attenuates contractile dysfunction in the remote left ventricle

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 290; no. 4; pp. H1410 - H1418
• Main Authors: Toufektsian, Marie-Claire, Yang, Zequan, Prasad, Konkal M, Overbergh, Lutgart, Ramos, Susan I, Mathieu, Chantal, Linden, Joel, French, Brent A
• Format: Journal Article
• Language: English
• Published: United States 01.04.2006
• Subjects: Animals; Cytokines - immunology; Mice; Myocardial Contraction - immunology; Myocardial Reperfusion Injury - complications; Myocardial Reperfusion Injury - immunology; Nitric Oxide Synthase Type II - immunology; Receptor, Adenosine A2A - immunology; Tissue Distribution; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - immunology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00860.2005

1 Department of Biomedical Engineering and 2 Division of Cardiovascular Medicine, University of Virginia, Charlottesville, Virginia; and 3 Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven, U.Z. Gasthuisberg, Leuven, Belgium Submitted 12 August 2005 ; accepted in final form 9 November 2005 Following myocardial infarction (MI), contractile dysfunction develops not only in the infarct zone but also in noninfarcted regions of the left ventricle remote from the infarct zone. Inflammatory activation secondary to MI stimulates inducible nitric oxide synthase (iNOS) induction with excess production of nitric oxide. We hypothesized that the anti-inflammatory effects of selective A 2A -adenosine receptor (A 2A AR) stimulation would suppress inflammation and preserve cardiac function in the remote zone early after MI. A total of 53 mice underwent 60 min of coronary occlusion followed by 24 h of reperfusion. The A 2A AR agonist (ATL146e, 2.4 µg/kg) was administered intraperitoneally 1, 3, and 6 h postreperfusion. Because of the 1-h delay in treatment after MI, ATL146e had no effect on infarct size, as demonstrated by contrast-enhanced cardiac MRI ( n = 18) performed 24 h post-MI. ATL146e did however preserve global cardiac function at that time by limiting contractile dysfunction in remote regions [left ventricle wall thickening: 51 ± 4% in treated ( n = 9) vs. 29 ± 3% in nontreated 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 noninfarcted zones. Similarly, elevations in plasma nitrate-nitrite after 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 noninfarcted regions ( P < 0.05). In conclusion, A 2A AR stimulation after MI suppresses inflammatory activation and preserves cardiac function, suggesting the potential utility of A 2A AR agonists against acute heart failure in the immediate post-MI period. magnetic resonance imaging; inflammation; nitric oxide synthase; nuclear factor- B activation; acute heart failure; left ventricular function Address for reprint requests and other correspondence: B. A. French, Dept. of Biomedical Engineering, Univ. of VA Health System, Box 800759, Charlottesville, VA 22908 (e-mail: bf4g{at}virginia.edu )