Abstract:
AIMS:Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown. METHODS AND RESULTS:To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harbouring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbour DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes. CONCLUSION:We provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Mezzano V,Liang Y,Wright AT,Lyon RC,Pfeiffer E,Song MY,Gu Y,Dalton ND,Scheinman M,Peterson KL,Evans SM,Fowler S,Cerrone M,McCulloch AD,Sheikh Fdoi
10.1093/cvr/cvw083subject
Has Abstractpub_date
2016-08-01 00:00:00pages
274-86issue
3eissn
0008-6363issn
1755-3245pii
cvw083journal_volume
111pub_type
杂志文章abstract:OBJECTIVES:Elevated systemic arterial blood pressure is associated with left ventricular hypertrophy and fibrosis. It has been suggested that both circulating and local myocardial renin-angiotensin systems play a role in mediating these responses. Here we describe the natural history of ventricular hypertrophy and fibr...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(00)00063-8
更新日期:2000-07-01 00:00:00
abstract::A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvp170
更新日期:2009-07-15 00:00:00
abstract::Mayer waves are oscillations of arterial pressure occurring spontaneously in conscious subjects at a frequency lower than respiration (approximately 0.1 Hz in humans). Mayer waves are tightly coupled with synchronous oscillations of efferent sympathetic nervous activity and are almost invariably enhanced during states...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2005.11.008
更新日期:2006-04-01 00:00:00
abstract:OBJECTIVE:The aim was to examine the effect of doxorubicin on spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum of skinned fibres, as measured by isometric tension development in EGTA free, Ca2+ free solution. METHODS:Experiments were done on fragments of papillary muscles from the right ventricles of gu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.4.371
更新日期:1992-04-01 00:00:00
abstract::Although the existence of t-tubules in mammalian cardiac ventricular myocytes has been recognized for a long time, it now appears that their structure and function are more complex than previously believed. Recent work has provided evidence that many of the key proteins underlying excitation-contraction coupling are l...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvm002
更新日期:2008-01-15 00:00:00
abstract:STUDY OBJECTIVE:The aim was to investigate observed differences in beta adrenergic and apparent non-beta-adrenergic binding of (-)[125I]-iodocyanopindolol (125I-ICYP). DESIGN:Binding parameters for several beta adrenergic agonists and antagonists were examined in radioligand binding assay, using 125I-ICYP as radioliga...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/25.9.764
更新日期:1991-09-01 00:00:00
abstract:OBJECTIVE:Washed platelets have been shown to protect isolated buffer perfused rat hearts from injury and dysfunction following ischaemia-reperfusion. This study was designed to investigate whether platelet glutathione redox cycle contributes to the protective effect of platelets. METHODS:Isolated rat hearts were perf...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.10.1586
更新日期:1994-10-01 00:00:00
abstract:OBJECTIVE:It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00149-1
更新日期:1997-11-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00469-3
更新日期:2003-09-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn043
更新日期:2008-06-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00185-x
更新日期:1997-01-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/25.6.463
更新日期:1991-06-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/19.9.528
更新日期:1985-09-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00270-3
更新日期:1999-04-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.06.028
更新日期:2005-05-01 00:00:00
abstract::Changes in left ventricular internal diameter resulting from increasing intrapericardial pressure induced by increasing the pericardial fluid volume were studied in closed chest, anaesthetized dogs. Left ventricular internal diameters were measured by placing an ultrasonic dimension catheter in the left ventricle at t...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/9.6.707
更新日期:1975-11-01 00:00:00
abstract:OBJECTIVE:To determine the role of calcineurin and Src tyrosine kinase in the regulation of inducible nitric oxide synthase (iNOS) expression and protection in cardiomyocytes. METHODS:iNOS expression was studied in isolated neonatal rat ventricular myocyte cultures in response to bacterial lipopolysaccharide (LPS) or ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2006.05.026
更新日期:2006-09-01 00:00:00
abstract::The effect of acetylcholine on the aconitine induced delayed afterdepolarisation and triggered electrical activities under nominally calcium free conditions were studied in frog atrium and ventricle. The changes in intracellular potassium activity were also examined. The aconitine induced delayed afterdepolarisation a...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/21.11.804
更新日期:1987-11-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/cvt043
更新日期:2013-06-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1016/s0008-6363(03)00522-4
更新日期:2003-10-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章,评审
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更新日期:2004-02-15 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2007.06.016
更新日期:2007-09-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn084
更新日期:2008-07-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/15.2.80
更新日期:1981-02-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/cvp380
更新日期:2010-04-01 00:00:00
abstract::Functional studies in extrarenal non-epithelial cells such as smooth muscle cells and easily accessible human lymphocytes have demonstrated that aldosterone not only produces classical genomic effects, but also rapid non-genomic effects on transmembrane electrolyte movements. These involve the activation of the Na+/H+...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:
更新日期:1995-02-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1016/j.cardiores.2003.08.006
更新日期:2003-11-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2005.06.008
更新日期:2005-10-01 00:00:00
abstract::Methodology has been developed for utilising ultrasonic crystals in closed chest cats to measure alterations in regional left ventricular function. The technique is a modification of one previously utilised to monitor regional left ventricular length and thickness changes in closed chest dogs. The ultrasonic crystals ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/12.6.387
更新日期:1978-06-01 00:00:00