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Deletion of Gja1 in myocardium emerges ventricular arrhythmia and tachycardia by reprogramming proline metabolism

ABSTRACT: Connexin43 (Cx43) is the predominant connexin in working myocardium. Its expression decreases in various cardiovascular diseases, and accompanied by ventricular arrhythmias (VAs). However, molecular mechanisms underlying increased arrhythmogenesis remained unclear. Here we established iPSC-derived cardiomyocytes (iPSC-CMs) and mouse models of Gja1 KO with proarrhythmic activity and disrupted proline metabolism. Mechanistically, Cx43 interacts with sodium-coupled neutral amino acid transporter 2 (SNAT2) where Gja1 KO reduces expression of SNAT2, leading to decreased proline and disrupted proline metabolism. Proline cycle in mitochondria preserves energetic/redox balance and exerts cardioprotective effects. Elevated reactive oxygen species (ROS) caused by disrupted proline metabolism leads to abnormal calcium handing and arrhythmia events. Taken together, the absence of Cx43 could facilitate the development of arrhythmias through reprogramming proline metabolism independent of reentry mechanisms, and indicated that molecular pathway of Cx43- SNAT2- ROS plays an essential role in maintaining normal cardiac rhythm.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS13302 | MetaboLights | 2025-11-11

REPOSITORIES: MetaboLights

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Project description:Note this data set has identical data files: Files GSM40994.txt and GSM40995.txt. GSE2240 contains two different experimental subsets:; 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium); The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005).

			Action	DRS
	Ctr-1_N.mzML	Mzml
	Ctr-1_P.mzML	Mzml
	Ctr-2_N.mzML	Mzml
	Ctr-2_P.mzML	Mzml
	Ctr-3_N.mzML	Mzml

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Deletion of Gja1 in myocardium emerges ventricular arrhythmia and tachycardia by reprogramming proline metabolism

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