MicroRNA-1976 regulates degeneration of the sinoatrial node by targeting Cav1.2 and Cav1.3 ion channels

Marked age- and development- related differences have been observed in morphology and characteristics of action potentials (AP) of neonatal and adult sinoatrial node (SAN) cells. These may be attributable to a different set of ion channel interactions between the different ages. However, the underlying mechanism(s) have yet to be elucidated. The objective of this study was to determine the mechanisms underlying different spontaneous APs and heart rate between neonatal and adult SAN cells of the rabbit heart by biophysical modeling approaches. A mathematical model of neonatal rabbit SAN cells was developed by modifying the current densities and/or kinetics of ion channels and transporters in an adult cell model based on available experimental data obtained from neonatal SAN cells. The single cell models were then incorporated into a multi-cellular, two-dimensional model of the intact SAN-atrium to investigate the functional impact of altered ion channels during maturation on pacemaking electrical activities and their conduction at the tissue level. Effects of the neurotransmitter acetylcholine on the pacemaking activities in neonatal cells were also investigated and compared to those in the adult. Our results showed: (1) the differences in ion channel properties between neonatal and adult SAN cells are able to account for differences in their APs and the heart rate, providing mechanistic insight into understanding the reduced pacemaking rate of the rabbit sinoatrial node during postnatal development; (2) in the 2D model of the intact SAN-atria, it was shown that cellular changes during postnatal development impaired pacemaking activity through increasing the activation time and reducing the conduction velocity across the SAN; (3) the neonatal SAN model, with its faster beating rates, showed a greater sensitivity to parasympathetic modulation in response to acetylcholine than did the adult model. These results provide novel insights into the understanding of the cellular mechanisms underlying the differences in the cardiac pacemaking activities of the neonatal and adult SAN.

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Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.662410 ◽

2021 ◽

Vol 8 ◽

Author(s):

Daniel Turner ◽

Chen Kang ◽

Pietro Mesirca ◽

Juan Hong ◽

Matteo E. Mangoni ◽

...

Keyword(s):

Signal Transduction ◽

Ion Channels ◽

Chloride Channels ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Sinoatrial Node ◽

Receptor Potential ◽

Past Century ◽

Transient Receptor

The understanding of the electrophysiological mechanisms that underlie mechanosensitivity of the sinoatrial node (SAN), the primary pacemaker of the heart, has been evolving over the past century. The heart is constantly exposed to a dynamic mechanical environment; as such, the SAN has numerous canonical and emerging mechanosensitive ion channels and signaling pathways that govern its ability to respond to both fast (within second or on beat-to-beat manner) and slow (minutes) timescales. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechanoactivated channels (Piezo, TREK, and BK) and slow mechanoresponsive ion channels [including volume-regulated chloride channels and transient receptor potential (TRP)], as well as the components of mechanochemical signal transduction, which may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechanochemical signal transduction and discuss the role of specialized membrane nanodomains, namely, caveolae, in mechanical regulation of both membrane and calcium clock components of the so-called coupled-clock pacemaker system responsible for SAN automaticity. Finally, we emphasize how these mechanically activated changes contribute to the pathophysiology of SAN dysfunction and discuss controversial areas necessitating future investigations. Though the exact mechanisms of SAN mechanosensitivity are currently unknown, identification of such components, their impact into SAN pacemaking, and pathological remodeling may provide new therapeutic targets for the treatment of SAN dysfunction and associated rhythm abnormalities.

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Cholinergic and Adrenergic Modulation of Ion Channels in a Rabbit Sinoatrial Node Model

IFAC Proceedings Volumes ◽

10.1016/s1474-6670(17)46163-5 ◽

1994 ◽

Vol 27 (1) ◽

pp. 67-68

Author(s):

Semahat S. Demir ◽

John W. Clark ◽

Wayne R. Giles

Keyword(s):

Ion Channels ◽

Sinoatrial Node ◽

Adrenergic Modulation ◽

Rabbit Sinoatrial Node

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β1-Adrenergic blocker bisoprolol reverses down-regulated ion channels in sinoatrial node of heart failure rats

Journal of Physiology and Biochemistry ◽

10.1007/s13105-016-0481-9 ◽

2016 ◽

Vol 72 (2) ◽

pp. 293-302 ◽

Cited By ~ 5

Author(s):

Yuan Du ◽

Junbo Zhang ◽

Yutao Xi ◽

Geru Wu ◽

Ke Han ◽

...

Keyword(s):

Heart Failure ◽

Ion Channels ◽

Sinoatrial Node ◽

Adrenergic Blocker

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Altered microRNA and mRNA profiles during heart failure in the human sinoatrial node

Scientific Reports ◽

10.1038/s41598-021-98580-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ning Li ◽

Esthela Artiga ◽

Anuradha Kalyanasundaram ◽

Brian J. Hansen ◽

Amy Webb ◽

...

Keyword(s):

Heart Failure ◽

Ion Channels ◽

Sinoatrial Node ◽

Molecular Targets ◽

Right Atrial ◽

Luciferase Reporter ◽

Mrna Targets ◽

Reporter Assays ◽

Multiple Signaling ◽

Generation Sequencing

AbstractHeart failure (HF) is frequently accompanied with the sinoatrial node (SAN) dysfunction, which causes tachy-brady arrhythmias and increased mortality. MicroRNA (miR) alterations are associated with HF progression. However, the transcriptome of HF human SAN, and its role in HF-associated remodeling of ion channels, transporters, and receptors responsible for SAN automaticity and conduction impairments is unknown. We conducted comprehensive high-throughput transcriptomic analysis of pure human SAN primary pacemaker tissue and neighboring right atrial tissue from human transplanted HF hearts (n = 10) and non-failing (nHF) donor hearts (n = 9), using next-generation sequencing. Overall, 47 miRs and 832 mRNAs related to multiple signaling pathways, including cardiac diseases, tachy-brady arrhythmias and fibrosis, were significantly altered in HF SAN. Of the altered miRs, 27 are predicted to regulate mRNAs of major ion channels and neurotransmitter receptors which are involved in SAN automaticity (e.g. HCN1, HCN4, SLC8A1) and intranodal conduction (e.g. SCN5A, SCN8A) or both (e.g. KCNJ3, KCNJ5). Luciferase reporter assays were used to validate interactions of miRs with predicted mRNA targets. In conclusion, our study provides a profile of altered miRs in HF human SAN, and a novel transcriptome blueprint to identify molecular targets for SAN dysfunction and arrhythmia treatments in HF.

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Cardiac Pacemaker Dysfunction Arising From Different Studies of Ion Channel Remodeling in the Aging Rat Heart

Frontiers in Physiology ◽

10.3389/fphys.2020.546508 ◽

2020 ◽

Vol 11 ◽

Author(s):

Aaazh M. Alghamdi ◽

Mark R. Boyett ◽

Jules C. Hancox ◽

Henggui Zhang

Keyword(s):

Ion Channels ◽

Sinoatrial Node ◽

Cardiac Pacemaker ◽

Data Sets ◽

Down Regulation ◽

Aged Rat ◽

Age Related ◽

Aging Study ◽

Ionic Mechanisms ◽

Induced Changes

The function of the sinoatrial node (SAN), the pacemaker of the heart, declines with age, resulting in increased incidence of sinoatrial node dysfunction (SND) in older adults. The present study assesses potential ionic mechanisms underlying age associated SND. Two group studies have identified complex and various changes in some of membrane ion channels in aged rat SAN, the first group (Aging Study-1) indicates a considerable changes of gene expression with up-regulation of mRNA in ion channels of Cav1.2, Cav1.3 and KvLQT1, Kv4.2, and the Ca2+ handling proteins of SERCA2a, and down-regulation of Cav3.1, NCX, and HCN1 and the Ca2+-clock proteins of RYR2. The second group (Aging Study-2) suggests a different pattern of changes, including down regulation of Cav1.2, Cav1.3 and HCN4, and RYR2, and an increase of NCX and SERCA densities and proteins. Although both data sets shared a similar finding for some specific ion channels, such as down regulation of HCN4, NCX, and RYR2, there are contradictory changes for some other membrane ion channels, such as either up-regulation or down-regulation of Cav1.2, NCX and SERCA2a in aged rat SAN. The present study aims to test a hypothesis that age-related SND may arise from different ionic and molecular remodeling patterns. To test this hypothesis, a mathematical model of the electrical action potential of rat SAN myocytes was modified to simulate the functional impact of age-induced changes on membrane ion channels and intracellular Ca2+ handling as observed in Aging Study-1 and Aging Study-2. The role and relative importance of each individually remodeled ion channels and Ca2+-handling in the two datasets were evaluated. It was shown that the age-induced changes in ion channels and Ca2+-handling, based on either Aging Study-1 or Aging Study-2, produced similar bradycardic effects as manifested by a marked reduction in the heart rate (HR) that matched experimental observations. Further analysis showed that although the SND arose from an integrated action of all remodeling of ion channels and Ca2+-handling in both studies, it was the change to ICaL that played the most important influence.

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