Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Laforest, Brigitte; Dai, Wenli; Tyan, Leonid; Lazarevic, Sonja; Shen, Karen; Gadek, Margaret; Broman, Michael; Weber, Christopher R.; Moskowitz, Ivan P.

doi:10.1172/jci124231

Cited by 29 publications

(42 citation statements)

References 77 publications

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“…Adult-specific removal of Tbx5 caused AF in mice and cardiomyocytes from this model revealed a multilevel gene regulatory network activated by TBX5 and repressed by PITX2 linking seven GWAS AF loci, including Scn5a, Atp2a2 and RyR2 [57]. A similar interaction has been identified through mouse genetics between Tbx5 and Gata4, with their interaction being crucial in atrial rhythm control via regulating the expression of Atp2a2 and RyR2 [58].…”

Section: Genetic Regulationsupporting

confidence: 56%

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

Beneke

Molina

2021

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Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase with the aging of the population and many important fundamental and translational underlaying mechanisms remain elusive. Here, we review recent advances in molecular and cellular basis for AF initiation, maintenance and progression. We first provide an overview of the basic molecular and electrophysiological mechanisms that lead and characterize AF. Next, we discuss the upstream regulatory factors conducting the underlying mechanisms which drive electrical and structural AF-associated remodeling, including genetic factors (risk variants associated to AF as transcriptional regulators and genetic changes associated to AF), neurohormonal regulation (i.e., cAMP) and oxidative stress imbalance (cGMP and mitochondrial dysfunction). Finally, we discuss the potential therapeutic implications of those findings, the knowledge gaps and consider future approaches to improve clinical management.

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Section: Genetic Regulationsupporting

confidence: 56%

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

Beneke

Molina

2021

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“…RyR2 and SERCA2a are two principal players in myocyte Ca cycling that are modulated physiologically, affected by disease and are considered as potential targets for therapy [1,3,19,20,[32][33][34]. However, how RyR2 and SERCA2a influence each other's activities under these various conditions remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Liu

Lou

Smith

et al. 2020

IJMS

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Ryanodine receptor 2 (RyR2) and SERCA2a are two major players in myocyte calcium (Ca) cycling that are modulated physiologically, affected by disease and thus considered to be potential targets for cardiac disease therapy. However, how RyR2 and SERCA2a influence each others’ activities, as well as the primary and secondary consequences of their combined manipulations remain controversial. In this study, we examined the effect of acute upregulation of SERCA2a on arrhythmogenesis by conditionally overexpressing SERCA2a in a mouse model featuring hyperactive RyR2s due to ablation of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies have shown that induction of SERCA2a (DOX+) overexpression markedly exacerbated both ventricular and atrial arrhythmias in vivo, compared with uninduced KO-TG mice (DOX-). Consistent with that, confocal microscopy in both atrial and ventricular myocytes demonstrated that conditional upregulation of SERCA2a enhanced the rate of occurrence of diastolic Ca release events. Additionally, deep RNA sequencing identified 17 downregulated genes and 5 upregulated genes in DOX+ mice, among which Ppp1r13l, Clcn1, and Agt have previously been linked to arrhythmias. Our results suggest that conditional upregulation of SERCA2a exacerbates hyperactive RyR2-mediated arrhythmias by further elevating diastolic Ca release.

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“…A following study revealed the involvement of Tbx5-dependent non-coding RNAs that were generated from enhancers and correlated with target gene expression [54]). Subsequent investigations found that atrial arrhythmias caused by Tbx5 deletion can be rescued by reduced Gata4 levels while Nkx2.5 was dispensable [55].…”

Section: Transcription Factors Involved In Atrial Development and Dismentioning

confidence: 99%

Four Dimensions of the Cardiac Myocyte Epigenome: from Fetal to Adult Heart

Rommel

Hein

2020

Curr Cardiol Rep

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Purpose of Review Development, physiological growth and the response of the heart to injury are accompanied by changes of the transcriptome and epigenome of cardiac myocytes. Recently, cell sorting and next generation sequencing techniques have been applied to determine cardiac myocyte-specific transcriptional and epigenetic mechanisms. This review provides a comprehensive overview of studies analysing the transcriptome and epigenome of cardiac myocytes in mouse and human hearts during development, physiological growth and disease. Recent Findings Adult cardiac myocytes express > 12,600 genes, and their expression levels correlate positively with active histone marks and inversely with gene body DNA methylation. DNA methylation accompanied the perinatal switch in sarcomere or metabolic isoform gene expression in cardiac myocytes, but remained rather stable in heart disease. DNA methylation and histone marks identified > 100,000 cis-regulatory regions in the cardiac myocyte epigenome with a dynamic spectrum of transcription factor binding sites. The ETS-related transcription factor ETV1 was identified as an atrial-specific element involved in the pathogenesis of atrial fibrillation. Summary Thus, dynamic development of the atrial vs. ventricular cardiac myocyte epigenome provides a basis to identify location and time-dependent mechanisms of epigenetic control to shape pathological gene expression during heart disease. Identifying the four dimensions of the cardiac myocyte epigenome, atrial vs. ventricular location, time during development and growth, and disease-specific signals, may ultimately lead to new treatment strategies for heart disease.

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Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Cited by 29 publications

References 77 publications

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Four Dimensions of the Cardiac Myocyte Epigenome: from Fetal to Adult Heart

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