Faculty Collaboration Database

Gene dosage-dependent effects of cardiac-specific overexpression of the A3 adenosine receptor. Circ Res 2002 Jul 26;91(2):165-72

Date

07/27/2002

Pubmed ID

12142350

Pubmed Central ID

PMC3682827

DOI

10.1161/01.res.0000028007.91385.ee

Scopus ID

2-s2.0-0037178739 (requires institutional sign-in at Scopus site)   79 Citations

Abstract

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 alpha-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 approximately 30% in A3tg.1 mice and approximately 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.

Author List

Black RG Jr, Guo Y, Ge ZD, Murphree SS, Prabhu SD, Jones WK, Bolli R, Auchampach JA

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine
Animals
Cardiotonic Agents
Echocardiography
Gene Dosage
Mice
Mice, Transgenic
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
RNA, Messenger
Receptor, Adenosine A3
Receptors, Purinergic P1