Abstract:
AIMS:The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr). Malfunction of hERG/IKr is the primary cause of acquired long QT syndrome (LQTS), an electrical disorder of the heart that can cause arrhythmias and sudden death. Patients with autoimmune diseases display a high incidence of LQTS. While dysfunction of hERG channels induced by autoantibodies such as anti-Ro52 may play a role in this pathology, the underlying mechanisms are not well understood. Here, we investigated the acute and chronic effects of anti-Ro52 antibody on hERG channels stably expressed in human embryonic kidney (hERG-HEK) 293 cells as well as IKr in neonatal rat ventricular myocytes. METHODS AND RESULTS:Using whole-cell patch clamp, western blot analyses, and immunocytochemistry, we found that a 12-h treatment of hERG-HEK cells with patients' sera containing anti-Ro52 autoantibody decreased the hERG current (IhERG) by 32% compared to cells treated with autoantibody-negative patients' sera. Commercial anti-Ro52 antibody at 100 µg/mL did not acutely block IhERG. Instead, a 12-h treatment with anti-Ro52 antibody at a concentration of 4 µg/mL significantly reduced mature hERG protein expression and IhERG. Specifically, anti-Ro52 antibody did not acutely block hERG current but chronically facilitated hERG endocytic degradation. The extracellular S5-pore linker of hERG, which forms the turret of the channel on the outside of the cell, is the target region for anti-Ro52-mediated hERG reduction since its replacement with the analogous region of EAG abolished the anti-Ro52 effect. In neonatal rat ventricular myocytes, 100 µg/mL anti-Ro52 antibody did not acutely block IKr, but a 12-h treatment of cells with 4 µg/mL anti-Ro52 antibody selectively reduced IKr and prolonged the action potential duration. CONCLUSIONS:Our results indicate that anti-Ro52 antibody acts on the hERG S5-pore linker to chronically decrease hERG expression and current. These findings provide novel insights into hERG regulation and anti-Ro52 antibody-associated LQTS.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Szendrey J,Lamothe SM,Vanner S,Guo J,Yang T,Li W,Davis J,Joneja M,Baranchuk A,Zhang Sdoi
10.1093/cvr/cvy310subject
Has Abstractpub_date
2019-08-01 00:00:00pages
1500-1511issue
10eissn
0008-6363issn
1755-3245pii
5244093journal_volume
115pub_type
杂志文章abstract:OBJECTIVE:Acute ischemia comes with two phases of life-threatening arrhythmias, early (within 10 minutes, 1A) and late (after about 15 minutes, 1B). The mechanism of the latter is unknown and in this paper, we test the hypothesis that a phase of intermediate coupling between surviving epicardium and inexcitable midmyoc...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00222-x
更新日期:2001-05-01 00:00:00
abstract:OBJECTIVE:Vascular responsiveness to vasoconstrictors is known to be attenuated in haemorrhagic shock. In this study we assessed the temporal development and the underlying mechanisms of haemorrhage-induced vascular hyporeactivity to pressor agents. METHODS:In phenobarbital-anaesthetised rats hypotension was induced b...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(99)00194-7
更新日期:1999-10-01 00:00:00
abstract:AIMS:The goal of this study was to determine whether the A1 adenosine receptor (AR) plays a role in atherosclerosis development and to explore its potential mechanisms. METHODS AND RESULTS:Double knockout (DKO) mice, deficient in the genes encoding A1 AR and apolipoprotein E (apoE), demonstrated reduced atheroscleroti...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu033
更新日期:2014-04-01 00:00:00
abstract:UNLABELLED:This study hypothesized that female patients with chronic heart failure (CHF), similarly as previously reported for male patients, have a decreased proportion of type I (slow twitch) muscle fibers combined with fiber atrophy, and respond to exercise training with an increased muscular fiber area and performa...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00313-7
更新日期:1999-04-01 00:00:00
abstract::The contractile response to beta-adrenoceptor stimulation has been found to be reduced in single myocytes from failing human ventricle. A portion of that reduction was statistically related to the age of the patient. We have developed a method for obtaining viable contracting myocytes from small biopsies of human vent...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1996-01-01 00:00:00
abstract::Numerous epidemiological studies documented an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the extent of atherosclerotic disease. However, clinical interventions targeting HDL cholesterol failed to show clinical benefits with respect to cardiovascular risk reduction, sugge...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvu136
更新日期:2014-08-01 00:00:00
abstract:AIMS:Placental growth factor (PlGF), a homologue of vascular endothelial growth factor, is a pleiotropic cytokine with a pro-inflammatory activity. Previous gene-inactivation studies revealed that the loss of PlGF delays atherosclerotic lesion development and inhibits macrophage infiltration, but the activity of an ant...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvp380
更新日期:2010-04-01 00:00:00
abstract:AIMS:A cytosolic calcium (Ca(2+)(i)) increase is an important activation signal for the endothelium. We investigated whether interendothelial spreading of the Ca(2+) signal via gap junctions (GJs) plays a role for the overall Ca(2+)(i) increase in response to vasoactive agonists. METHODS AND RESULTS:In human umbilical...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvr345
更新日期:2012-03-01 00:00:00
abstract::In isolated electrically stimulated guinea pig papillary muscles tiapamil exerts a negative inotropic action that corresponds to its presumptive inhibitory effects on the slow-channel-mediated transmembrane Ca2+ influx. However, contractile depression is always accompanied by marked alterations of the normal Na+-carri...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.1.42
更新日期:1986-01-01 00:00:00
abstract:AIMS:In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebra...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvaa238
更新日期:2020-07-31 00:00:00
abstract::The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptor...
journal_title:Cardiovascular research
pub_type: 评论,杂志文章,评审
doi:10.1016/s0008-6363(99)00319-3
更新日期:2000-01-01 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:OBJECTIVES:Plasma endothelin (ET) concentrations are increased in heart failure. The aims of the present study were to investigate to what extent cardiac ET mRNA expression is induced in ischemic heart failure and whether there may be compensatory downregulation of myocardial mRNA levels for the ETA and ETB receptor su...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00266-0
更新日期:1997-03-01 00:00:00
abstract:AIMS:Cathepsin-L (CTSL) is a member of the lysozomal cysteine protease family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of CTSL in cardiac remodelling post-infarction. METHODS AND RESULTS:Experimental myocardial infarction (MI) was created in CTSL-defi...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvq328
更新日期:2011-02-01 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::The theoretical possibilities and the practical limitations of the Xenon-133 (133Xe) method for the study of regional myocardial perfusion in man are discussed. The techniques for data acqusition and processing developed over the past 5 years are described in detail. Illustrative examples of experimental findings are ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/11.4.277
更新日期:1977-07-01 00:00:00
abstract:AIMS:Although the use of drug-eluting stents (DESs) has been shown to limit neointima hyperplasia, currently available DESs may adversely affect re-endothelialization. To evaluate whether a novel gene silencer pyrrole-imidazole (PI) polyamide targeting transforming growth factor (TGF)-beta1 is a candidate agent for the...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn355
更新日期:2009-03-01 00:00:00
abstract:OBJECTIVE:The aim of this study was to examine the effect of ischaemia on vascular responses to endothelium-dependent and endothelium-independent vasodilators and on vasoconstrictor responses. Furthermore, the ability of preconditioning to prevent ischaemia-induced changes in vascular reactivity was examined in the rat...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00167-8
更新日期:1996-12-01 00:00:00
abstract::The static elastic properties of the aorta ad systolic blood pressure in the caudal artery have been measured in 55 spontaneously hypertensive rats of the AS strain. Animals were divided into five groups and treated from the age of 4 to 12 weeks as follows: (1) 0.25 mm silver clip positioned around the right renal art...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/15.7.373
更新日期:1981-07-01 00:00:00
abstract:AIMS:SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage. METHODS AND ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvz138
更新日期:2020-03-01 00:00:00
abstract:OBJECTIVES:The purpose of this study was to investigate the changes in beta-adrenoceptor density (Bmax) and distribution in a model of chronic myocardial infarction in rats, and to relate possible changes to hemodynamic and neurohumoral abnormalities. In addition, we examined the effects of 8 weeks treatment with ibopa...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::Injudicious selection of a saphenous vein graft can adversely affect the the late postoperative patency of the proximal coronary artery which it bypasses. The purpose of this investigation was to deduce an upper bound for graft diameter, at small angle of distal anastomosis, below which the stenosed artery will remain...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.7.370
更新日期:1979-07-01 00:00:00
abstract:AIMS:Angiotensin II is a potential contributor to the development of abdominal aortic aneurysm (AAA). In aortic vascular smooth muscle cells, exposure to angiotensin II induces mitochondrial fission via dynamin-related protein 1 (Drp1). However, pathophysiological relevance of mitochondrial morphology in angiotensin II...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvaa133
更新日期:2020-05-08 00:00:00
abstract:OBJECTIVE:Decay kinetics of the voltage-gated L-type Ca(2+) current (I(CaL)) control the magnitude of Ca(2+) influx during the cardiac action potential. We investigated the influence of changes in diastolic membrane potential on I(CaL) decay kinetics in cardiac cells. METHODS:Cells were isolated enzymatically from rat...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(00)00107-3
更新日期:2000-08-01 00:00:00
abstract:OBJECTIVES:L-arginine exerts anti-atherosclerotic effects in hypercholesterolaemic rabbits via modulating endogenous NO production. We investigated whether L-arginine inhibits thromboxane formation in vivo and platelet aggregation ex vivo in this animal model. METHODS:The urinary excretion rates of 2,3-dinor-6-keto-PG...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00295-2
更新日期:1998-03-01 00:00:00
abstract::Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.10.721
更新日期:1986-10-01 00:00:00
abstract:OBJECTIVE:In diabetes mellitus several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models changes in these parameters were reported, but no such data are available in other mammalian species including the dog. The present study was designed to analyse the effects of...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2006.11.010
更新日期:2007-02-01 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::Elevated sympathetic activity changes renal function and accelerates the development of hypertension. Principles of sympatho-renal interactions in chronic hypertension are reviewed. Alterations in the ontogeny of the sympathetic nervous system and the kidney, inherited abnormalities in sensory receptor function and ex...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2003.11.024
更新日期:2004-02-01 00:00:00
abstract::The purpose of this review is to give an integrative view of the effect of stretch on the myocardium from ventricular function changes to cellular and molecular mechanisms. The general approach will be to discuss the cellular and molecular events which can explain the findings obtained in the whole ventricle. Followin...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:
更新日期:1996-07-01 00:00:00