Abstract-We used a genetic approach to determine whether increasing the level of A 3 adenosine receptors (A 3 ARs) expressed in the heart confers protection against ischemia without causing cardiac pathology. We generated mice carrying one (A 3 tg.1) or six (A 3 tg.6) copies of a transgene consisting of the cardiomyocyte-specific ␣-myosin heavy chain gene promoter and the A 3 AR cDNA. A 3 tg.1 and A 3 tg.6 mice expressed 12.7Ϯ3.15 and 66.3Ϯ9.4 fmol/mg of the high-affinity G protein-coupled form of the A 3 AR in the myocardium, respectively. Extensive morphological, histological, and functional analyses demonstrated that there were no apparent abnormalities in A 3 tg.1 transgenic mice compared with nontransgenic mice. In contrast, A 3 tg.6 mice exhibited dilated hearts, expression of markers of hypertrophy, bradycardia, hypotension, and systolic dysfunction. When A 3 tg mice were subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion, infarct size was reduced Ϸ30% in A 3 tg.1 mice and Ϸ40% in A 3 tg.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 A 3 AR signaling in the ischemic myocardium. The results demonstrate that low-level expression of A 3 ARs in the heart provides effective protection against ischemic injury without detectable adverse effects, whereas higher levels of A 3 AR expression lead to the development of a dilated cardiomyopathy.

The results demonstrate that in vivo gene transfer of the cDNA encoding Ec-SOD provides the heart with substantial protection against myocardial stunning without the need for concomitant administration of catalase. The present observations provide the basis for controlling gene therapy at the posttranslational level and for simultaneously protecting multiple organs from oxidant stress.

Background-A new intracellular adenosine triphosphate (ATP) delivery technique has been developed and was tested for skin wound care.