Abstract 18084: Systematic Analysis of Gene Expression Differences Between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue

Abstract

Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (Paired-like homeodomain transcription factor2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. To characterize differences between left and right atrium in adult hearts, we systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria. Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains (MF1, 3 months old; MF1, 12 months old; Swiss Agouti, 12 months old) by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in right or left atrium were validated by RT-qPCR in further animals, and by RT-qPCR and Western blot in shock-frozen left and right atrial appendages of patients undergoing open heart surgery. Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10 (Bone morphogenetic protein 10) showed enrichment in right atrium, consistent with prior reports. Nine selected genes, including Pitx2c, were validated by RT-qPCR in murine tissue, and five orthologous genes in human tissue. Western blot showed a 2-fold left-right ratio in PITX2c protein in adult human atria. Several of the genes and gene groups enriched in left atria have a reasonable biological role for the prevention of atrial pathology including atrial fibrillation, membrane electrophysiology, metabolic cellular function, and regulation of inflammatory cells. Comparison of the array data sets with published array analyses in heterozygous pitx2+/- atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c. Conclusions: Our study reveals systematic differences between left and right atrial gene expression during adulthood and supports the hypothesis that Pitx2c has a functional role in maintaining “leftness” in the atrium in adult mice and humans.