Connexins and the atrioventricular node

The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles. It is shown that the complex patterning of connexins is the consequence of the embryonic development of the cardiac conduction system. Finally, it is argued that connexin dysregulation may be responsible for AV node dysfunction

Atrioventricular node dysfunction in pressure overload-induced heart failure—Involvement of the immune system and transcriptomic remodelling

Heart failure is associated with atrioventricular (AV) node dysfunction, and AV node dysfunction in the setting of heart failure is associated with an increased risk of mortality and heart failure hospitalisation. This study aims to understand the causes of AV node dysfunction in heart failure by studying changes in the whole nodal transcriptome. The mouse transverse aortic constriction model of pressure overload-induced heart failure was studied; functional changes were assessed using electrocardiography and echocardiography and the transcriptome of the AV node was quantified using RNAseq. Heart failure was associated with a significant increase in the PR interval, indicating a slowing of AV node conduction and AV node dysfunction, and significant changes in 3,077 transcripts (5.6% of the transcriptome). Many systems were affected: transcripts supporting AV node conduction were downregulated and there were changes in transcripts identified by GWAS as determinants of the PR interval. In addition, there was evidence of remodelling of the sarcomere, a shift from fatty acid to glucose metabolism, remodelling of the extracellular matrix, and remodelling of the transcription and translation machinery. There was evidence of the causes of this widespread remodelling of the AV node: evidence of dysregulation of multiple intracellular signalling pathways, dysregulation of 109 protein kinases and 148 transcription factors, and an immune response with a proliferation of neutrophils, monocytes, macrophages and B lymphocytes and a dysregulation of 40 cytokines. In conclusion, inflammation and a widespread transcriptional remodelling of the AV node underlies AV node dysfunction in heart failure

MiR-486-3p and MiR-938—Important Inhibitors of Pacemaking Ion Channels and/or Markers of Immune Cells

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-26, pub-electronic 2021-12-01Publication status: PublishedFunder: British Heart Foundation; Grant(s): FS/17/67/33483Funder: Fondation Leducq; Grant(s): THE FANTACY 19CVD03The sinus node (SN) is the heart’s primary pacemaker and has a unique expression of pacemaking ion channels and immune cell markers. The role of microribonucleic acids (miRNAs) in control of ion channels and immune function of the sinus node is not well understood. We have recently shown that hsa-miR-486-3p downregulates the main pacemaking channel HCN4 in the SN. In addition, we recently demonstrated that immune cells are significantly more abundant in the SN compared to the right atrium. The aim of this study was to validate the previously predicted interactions between miRNAs and mRNAs of key Ca2+ ion channels (involved in peacemaking) and mRNA of TPSAB1—(a mast cells marker) using luciferase assay. We now show that miR-486 significantly downregulates Cav1.3, Cav3.1, and TPSAB1-mediated luciferase activity, while miR-938 significantly downregulates only TPSAB1-mediated luciferase activity. This makes miR-486-3p a potential therapeutic target in the treatment of SN dysfunctions

Pilot erfemissie van bloembollenbedrijven in Noord-Holland (Breezand)

In het Noordelijk Zandgebied in Noord-Holland worden voor enkele gewasbeschermingsmiddelen de waterkwaliteitsnormen (MTR) geregeld overschreden. In 2009 zijn telers uit een deel van de Westpolder van Anna Paulowna in de Kop van Noord Holland een samenwerkingsproject gestart om inzicht te krijgen in emissieroutes van gewasbeschermingsmiddelen vanaf het erf om daarmee emissie via deze routes te voorkomen en de waterkwaliteit in de polder te verbeteren. Eind 2010 hebben zich vier gewasbeschermingsmiddelenfabrikanten aangesloten bij de samenwerking: Certis, Bayer, Syngenta en BASF

Identification of key small non-coding MicroRNAs controlling pacemaker mechanisms in the human sinus node

BACKGROUND: The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potential morphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca2+-handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible for human SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profile of the human SN as compared with that of non-pacemaker atrial muscle. METHODS AND RESULTS: SN and atrial muscle biopsies were obtained from donor or post-mortem hearts (n=10), histology/ immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs, Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR-486-3p predicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization-activated cyclic nucleotide-gated 1), HCN4, voltage-gated calcium channel (Cav )1.3, and Cav 3.1. A luciferase reporter gene assay confirmed that miR-486-3p can control HCN4 expression via its 3′ untranslated region. In ex vivo SN preparations, transfection with miR-486-3p reduced the beating rate by ≈35±5% (P<0.05) and HCN4 expression (P<0.05). CONCLUSIONS: The human SN possesses a unique pattern of expression of miRs predicted to target functionally important genes. miR-486-3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.</p