Published online before print June 27, 2002, doi: 10.1161/01.RES.0000028007.91385.EE
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Submitted on October 19, 2001
Revised on June 19, 2002
Accepted on June 19, 2002
Gene Dosage Dependent Effects of Cardiac-Specific Overexpression of the A3 Adenosine Receptor
Richard G. Black Jr ;
From the Department of Pharmacology and Toxicology and the Cardiovascular Research Center (Z.-D.G., J.A.A.), Medical College of Wisconsin, Milwaukee, Wis; the Departments of Medicine (Cardiology) (R.G.B., Y.G., S.D.P., R.B., J.A.A.) and Pathology (S.S.M.), University of Louisville, Louisville, Ky; and the Department of Molecular Pharmacology and Cellular Biophysics (W.K.J.), University of Cincinnati, Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: jauchamp{at}mcw.edu.
We used a genetic approach to determine whether increasing the level of A3 adenosine receptors (A3ARs) expressed in the heart confers protection against ischemia without causing cardiac pathology. We generated mice carrying one (A3tg.1) or six (A3tg.6) copies of a transgene consisting of the cardiomyocyte-specific 
-myosin heavy chain gene promoter and the A3AR cDNA. A3tg.1 and A3tg.6 mice expressed 12.7±3.15 and 66.3±9.4 fmol/mg of the high-affinity G protein--coupled form of the A3AR in the myocardium, respectively. Extensive morphological, histological, and functional analyses demonstrated that there were no apparent abnormalities in A3tg.1 transgenic mice compared with nontransgenic mice. In contrast, A3tg.6 mice exhibited dilated hearts, expression of markers of hypertrophy, bradycardia, hypotension, and systolic dysfunction. When A3tg mice were subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion, infarct size was reduced 
30% in A3tg.1 mice and 40% in A3tg.6 mice compared with nontransgenic littermates. The reduction in infarct size in the transgenic mice was not related to differences in risk region size, systemic hemodynamics, or body temperature, indicating that the cardioprotection was a result of increased A3AR signaling in the ischemic myocardium. The results demonstrate that low-level expression of A3ARs in the heart provides effective protection against ischemic injury without detectable adverse effects, whereas higher levels of A3AR expression lead to the development of a dilated cardiomyopathy.
Key words: adenosine receptors • ischemia • transgenic mice • heart
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