Abstract 878: Wild Type A1 Adenosine Receptor and a Mutated A1 Adenosine Receptor Differentially Induced Cardiomyopathy Gene Expression In Transgenic Mouse Hearts
A1 adenosine receptor (A1-AR) regulates both physiological and pathological functions in the heart. The specific signaling pathways responsible for these opposite functions remain poorly understood. After identifying a mutated form of A1-AR with four amino acid altering mutations (mutA1-AR: 89 t-c, 521 t-a, 781 c-t, 863 a-g) from a human tumor, we compared the biochemical and physiological properties of mutA1-AR to the wild type receptor in transgenic mouse hearts. We overexpressed both wild type and mutant A1-AR in transgenic mouse hearts using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. Both transgenic types (wtA1-TG and mutA1-TG) expressed receptor at 150–300 fold above the endogenous level. However, 50% of the mutant A1-AR migrated as high molecular weight bands under non-reducing conditions and showed higher binding affinity for the selective A1 antagonist DPCPX. Phenotypical characterization showed that constitutive expression of wild type A1-AR induced dilated cardiomyopathy with poor survival, whereas all mutA1-TG survived past 10 weeks. Gene expression studies showed that both wtA1-TG and mutA1-TG induced the expression of the same cardiomyopathy associated genes (A/BNP, and Collagen 1a). However, mutant A1-AR selectively failed to inhibit the calcium handling gene, SERCA2a (WT: 7.0+/− 2.1; wtA1-TG: 1.2+/−0.6; mutA1-TG: 7.5+/−1.1). Our data suggested that A1-AR mutation may specifically alter receptor signaling to SERCA2a and may account for the milder cardiomyopathy phenotype found in the mutA1-TG. These studies may help to elucidate the mechanisms by which A1-AR elicits cardioprotection and cardiomyopathy.