Clin Res Cardiol 100, Suppl 1, April 2011

P648 - Systematic analysis of differences in right and left atrial gene expression during adulthood - evidence of a continuing left atrial function of transcription factor PITX2c
P. C. Kahr1, P. Ilaria1, H. Rotering2, H. H. Scheld2, G. Boris3, N. A. Brown4, L. Fabritz1, P. Kirchhof1
1Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, Münster; 2Klinik u. Polikl. f. Herz-, Thorax- u. Gefäßchirurgie, Universitätsklinikum Münster, Münster; 3Human Stem Cell Plurypotency Group, Max-Planck-Institut für molekulare Biomedizin, Münster; 4Division of Biomedical Sciences, St. George's, University of London, London, Großbritannien;
Introduction: The heart is morphologically and functionally left-right (L/R) asymmetric. In particular, atrial rhythm seems to be defined asymmetrically - with the physiological pacemaker being in the right atrium (RA) and most triggers for atrial fibrillation in the left atrium (LA). Interestingly, one of the genes that is known to orchestrate left-right differences during cardiac embryonal development, PITX2c, has recently been associated with atrial fibrillation in several genome-wide association studies. We therefore systematically characterized differences in gene expression between left and right atria to identify potential factors for atrial fibrillation.
Methods: We analyzed the transcriptome of LA and RA from two different mouse strains at two different ages (MF1, 3-month-old, n=5; Swiss Agouti, 12-month-old, n=4) using mRNA expression arrays. Selected genes were validated by RT-qPCR in further animals from both strains (n=4, each), plus a third strain (CD1, 6-month-old, n=4) and human samples from right and left atrial appendages (n=5) of patients aged 69 ± 14 (SEM) years. All pairs of right and left human atrial samples were harvested during a single open-heart operation and shock-frozen immediately after harvesting. Western blot analysis was performed on the same human samples (n=5).
Results: Statistical analysis revealed 493 gene probes as being significantly different between LA and RA in MF1 and Swiss Agouti microarrays. In both strains / time-points, PITX2c was the most differentially expressed gene with left-sided predominance (>100-fold). It is opposed by Bmp10 (Bone morphogenic protein 10) as the most differentially expressed gene with right atrial predominance. Among other gene groups, we found ion channel genes, ion-channel regulators, transcription factors and growth factor binding proteins as being differentially expressed between left and right atria. Functioncal and Gene Set Enrichment Analysis (FatiGO and GSEA) consistently revealed several asymmetrical mitochondrial gene clusters in both mouse-models and time-points. 10 genes including PITX2 and BMP10 were validated by RT-qPCR in both strains and additionally in CD1 mice with full concordance in all genes and all models. RT-qPCR measurements in human atrial appendages could reproduce differential expression in 6 of 9 tested genes. Furthermore, we confirmed a higher expression of PITX2c in the left atrium compared to the right atrium by Western Blot in human tissue.
Conclusions: In tissues from different mouse strains and age groups, we identified molecular and potentially relevant L/R differences in murine atrial mRNA expression during adulthood. From successfully validated genes we conclude that these differences might be similar in humans. Of note, PITX2c is the single most importantly differentially expressed gene in the left atrium, supportive of a continuing physiological left atrial PITX2c function beyond development. If PITX2c were linked to the genesis of atrial fibrillation, its left atrial expression may explain why atrial fibrillation often originates in the left atrium.
Clin Res Cardiol 100, Suppl 1, April 2011
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-011-1100-y