Abstract：
AIMS:The molecular mechanisms controlling heart function and rhythmicity are incompletely understood. While it is widely accepted that the type 2 ryanodine receptor (Ryr2) is the major Ca(2+) release channel in excitation-contraction coupling, the role of these channels in setting a consistent beating rate remains controversial. Gain-of-function RYR2 mutations in humans and genetically engineered mouse models are known to cause Ca(2+) leak, arrhythmias, and sudden cardiac death. Embryonic stem-cell derived cardiomyocytes lacking Ryr2 display slower beating rates, but no supporting in vivo evidence has been presented. The aim of the present study was to test the hypothesis that RYR2 loss-of-function would reduce heart rate and rhythmicity in vivo. METHODS AND RESULTS:We generated inducible, tissue-specific Ryr2 knockout mice with acute ∼50% loss of RYR2 protein in the heart but not in other tissues. Echocardiography, working heart perfusion, and in vivo ECG telemetry demonstrated that deletion of Ryr2 was sufficient to cause bradycardia and arrhythmia. Our results also show that cardiac Ryr2 knockout mice exhibit functional and structural hallmarks of heart failure, including sudden cardiac death. CONCLUSION:These results illustrate that the RYR2 channel plays an essential role in pacing heart rate. Moreover, we find that RYR2 loss-of-function can lead to fatal arrhythmias typically associated with gain-of-function mutations. Given that RYR2 levels can be reduced in pathological conditions, including heart failure and diabetic cardiomyopathy, we predict that RYR2 loss contributes to disease-associated bradycardia, arrhythmia, and sudden death.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Bround MJ,Asghari P,Wambolt RB,Bohunek L,Smits C,Philit M,Kieffer TJ,Lakatta EG,Boheler KR,Moore ED,Allard MF,Johnson JDdoi
10.1093/cvr/cvs260subject
Has Abstractpub_date
2012-12-01 00:00:00pages
372-80issue
3eissn
0008-6363issn
1755-3245pii
cvs260journal_volume
96pub_type
杂志文章abstract：BACKGROUND:Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-gamma ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(03)00457-7
更新日期：2003-09-01 00:00:00
abstract：AIMS:Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit skeletal muscle or pig cardiac muscle, respectively. In heart failure,...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvp273
更新日期：2010-01-01 00:00:00
abstract：:One of the striking differences that distinguish the adult from the embryonic heart in mammals and set it apart from the heart in urodeles and teleosts is the incapacity of cardiomyocytes to respond to damage by proliferation. While the molecular reasons underlying these characteristics still await elucidation, mounti...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvu057
更新日期：2014-05-01 00:00:00
abstract：CONDENSED ABSTRACT:We analyzed actomyosin cross-bridge kinetics in human atrial and ventricular muscle strip preparations by using sinusoidal length changes from 0.1 to 60 Hz. The minimum stiffness frequency was higher in atrial than in ventricular human myocardium and lower in failing than in non-failing left ventricu...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(98)00164-3
更新日期：1998-12-01 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
abstract：OBJECTIVE:Activin-like kinase receptor 1 (ALK1) is a transforming growth factor (TGF)-beta type I receptor expressed in vascular mesenchyme, yet its function in vascular mesenchymal cells (VMC) is unclear. We examined ALK1 expression in human coronary atherosclerotic lesions and bovine and human VMC undergoing cellular...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2006.09.014
更新日期：2007-05-01 00:00:00
abstract：OBJECTIVES:The concept of lethal reperfusion injury in ischemic myocardium has been the subject of controversy. Adenosine administered during reperfusion has been reported to limit lethal reperfusion injury in several studies. On the contrary, it has been reported that cardioprotection may not be achieved with adenosin...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/0008-6363(95)00235-9
更新日期：1996-05-01 00:00:00
abstract：BACKGROUND:A recent genome-wide association study identified a susceptibility locus for atrial fibrillation at the KCNN3 gene. Since the KCNN3 gene encodes for a small conductance calcium-activated potassium channel, we hypothesized that overexpression of the SK3 channel increases susceptibility to cardiac arrhythmias....
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvt269
更新日期：2014-02-01 00:00:00
abstract：:The structural basis for the development of congestive heart failure (CHF) is a maladaptive myocardial remodeling process which occurs secondarily to post-myocardial infarction (MI), hypertensive hypertrophy, or cardiomyopathy. Both cellular and extracellular factors are involved in the remodeling process and it is th...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2005.10.004
更新日期：2006-02-15 00:00:00
abstract：OBJECTIVES:Conduction of vasoconstrictor and vasodilator responses in the microcirculation involves electrical coupling through gap junction channels among cells of the vascular wall. The present study determined whether reported differences in the properties of conduction along the arterioles of the epithelial hamster...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2003.09.017
更新日期：2003-12-01 00:00:00
abstract：OBJECTIVE:Lipoprotein lipase (LPL) mediated hydrolysis of circulating triglyceride (TG)-rich lipoproteins provides the heart with fatty acids. The present study was designed to investigate the influence of circulating TG and their lipolysis in facilitating translocation of LPL from the underlying cardiomyocyte cell sur...
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
abstract：Aims:Dilated cardiomyopathy (DCM) induced chronic heart failure is a life-threatening disease worldwide. Long non-coding RNAs (lncRNAs) are potential new therapeutic targets and may provide new pathophysiological mechanisms for development of DCM. Methods and results:Microarray assays in 14 DCM and 10 control human he...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvy012
更新日期：2018-04-01 00:00:00
abstract：OBJECTIVE:To investigate the effect of the ATP-sensitive potassium (KATP) channel inhibitor sodium 5-hydroxydecanoate (5-HD) on the reduction in myocardial infarct size afforded by ischaemic preconditioning in the sodium pentobarbitone rabbit. METHODS:New Zealand white rabbits were anaesthetised with sodium pentobarbi...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：
更新日期：1996-06-01 00:00:00
abstract：OBJECTIVE:Catechol O-methyltransferase (COMT) is believed to exert degradative action at high norepinephrine (NE) levels. Although COMT exists in cardiac tissues, the contribution of cardiac COMT activity to regional NE kinetics, particularly in ischemia-induced NE accumulation, remains unclear. We investigated the rol...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2004.06.011
更新日期：2004-10-01 00:00:00
abstract：:Intracellular acidosis exerts substantial effects on the contractile performance of the heart. Soon after the onset of acidosis, contractility diminishes, largely due to a decrease in myofilament Ca(2+) responsiveness. This decrease in contractility is followed by a progressive recovery that occurs despite the persist...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2006.12.002
更新日期：2007-03-01 00:00:00
abstract：:This review attempts to define the early events that lead to lesions of human atherosclerosis based on careful morphological studies in human autopsy specimens. In contrast to most small laboratory animals, diffuse intimal thickening (DIT) is present in human arteries before atherosclerosis develops, particularly in t...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvn099
更新日期：2008-07-01 00:00:00
abstract：OBJECTIVES:M cells have been described in many mammalian species. They are thought to be relevant for the genesis of long QT intervals, afterdepolarizations and for dispersion in action potential duration and in repolarization time. Their role in the human heart is subject to debate. METHODS:We simulated action potent...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2004.02.016
更新日期：2004-05-01 00:00:00
abstract：OBJECTIVE:The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evalua...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(98)00152-7
更新日期：1998-09-01 00:00:00
abstract：AIMS:Altered Ca(2+) handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvu123
更新日期：2014-07-01 00:00:00
abstract：:Muscle tissue in atrioventricular (A-V) cardiac valve leaflets was studied in 35 human hearts and was found to be more prominent in the anterior leaflet of the mitral (MAL) than in the other valve leaflets. From serial sectioning and wax model reconstruction, the anatomic arrangement of the muscle in the MAL indicates...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/12.11.675
更新日期：1978-11-01 00:00:00
abstract：OBJECTIVE:The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2007.03.027
更新日期：2007-07-01 00:00:00
abstract：OBJECTIVE:Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and may be involved in the rupture of atherosclerotic plaques by degrading fibrous cap, resulting in the intravascular thrombus formation. Here we examined whether local overexpression of MMP-9 alters the characteristics of arteriosclerot...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(02)00710-1
更新日期：2003-02-01 00:00:00
abstract：AIMS:Atrial fibrillation (AF) is the most common type of arrhythmia in humans, yet the genetic cause of AF remains elusive. Genome-wide association studies (GWASs) have reported risk variants in four distinct genetic loci, and more recently, a meta-GWAS has further implicated six new loci in AF. However, the functional...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvv207
更新日期：2016-01-01 00:00:00
abstract：BACKGROUND:The mechanism of defibrillation is controversial. Reentry appearing immediately after the shock has been shown to be responsible for defibrillation failure in some studies while other studies have demonstrated that a rapid train of focal activations with the first focus appearing >50 ms after the shock is re...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2003.10.009
更新日期：2004-01-01 00:00:00
abstract：:To test hypothesis that adrenergic neurotransmission is impaired in acute myocardial ischaemia, we studied contractile function of normal and ischaemic myocardium after coronary artery occlusion. For each area we compared the contractile response to left sympathetic nerve stimulation (LSS) with the response to exogeno...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/14.2.116
更新日期：1980-02-01 00:00:00
abstract：AIMS:We analysed the possible protective role of human endothelial (EPCs) and smooth muscle (SPCs) progenitor cells on atherosclerosis development in apoE(-/-)RAG2(-/-) mice. We determined plasma levels of SPCs in coronary patients. METHODS AND RESULTS:ApoE(-/-)RAG2(-/-) mice received four intravenous injections of sa...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvm034
更新日期：2008-02-01 00:00:00
abstract：STUDY OBJECTIVE:Afterload reduction is known to reduce regurgitant flow in patients with aortic regurgitation. Both arterial compliance and total peripheral resistance are determinants of afterload. The aim of this study was to evaluate the influence of arterial compliance and total peripheral resistance on the regurgi...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/25.10.869
更新日期：1991-10-01 00:00:00
abstract：:In this review, we summarize current knowledge on the genetics of coronary artery disease, based on 10 years of genome-wide association studies. The discoveries began with individual studies using 200K single nucleotide polymorphism arrays and progressed to large-scale collaborative efforts, involving more than a 100 ...
journal_title：Cardiovascular research
pub_type： 历史文章,杂志文章,评审
doi：10.1093/cvr/cvy084
更新日期：2018-07-15 00:00:00
abstract：OBJECTIVE:Although aldosterone has been implicated in the pathogenesis of cardiac hypertrophy and heart failure, its cellular mechanism of action on cardiomyocyte function is not yet completely elucidated. This study was designed to investigate the effect of aldosterone on calcium channel expression and cardiomyocyte c...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2005.05.009
更新日期：2005-08-01 00:00:00
abstract：:The effect of axial rotation on flow through and pressure gradient across saphenous vein segments was studied using 15 cadaver long saphenous veins. A significant reduction in flow occurred at a mean rotation of 25 degrees/cm and a significant increase in head loss across the segments occurred at a mean rotation of 23...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/9.4.538
更新日期：1975-07-01 00:00:00
