Abstract
BackgroundNormal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.MethodsWe compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.ResultsWe 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, a member of the TGFβ family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c+/− atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.ConclusionsOur study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining “leftness” in the atrium in adult murine and human hearts.
Highlights
Atrial fibrillation is the most common sustained arrhythmia [1,2,3,4]
Gene Set Enrichment Analysis To investigate the potential relevance of differentially expressed genes in left and right atrium without preformed hypotheses, we performed gene set enrichment analyses (GSEA) in each of the datasets independently
We identified a total of 119 differentially expressed Gene Ontology (GO) terms, with the majority of these enriched in right atrium (77 terms) and in the MF1_3 dataset (107 terms, Supplementary Table S2)
Summary
Atrial fibrillation is the most common sustained arrhythmia [1,2,3,4]. Several forms of atrial damage, including electrical and structural ‘‘remodelling’’, are the main cause of atrial fibrillation [5,6]. It is generally accepted that atrial fibrillation is mainly a left atrial disease. This old concept has been reinforced by the development of ablation techniques to eliminate left atrial triggers of atrial fibrillation [7], by recent analyses of ion channel expression and function in left and right atria [8], and by the identification of rare somatic mutations in left atrial myocardium associated with atrial fibrillation [9]. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria
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