Abstract:
AIMS:For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long-term progress of non-structural cardiac diseases. The aim of the present study is to define the postnatal epigenome of two common cardiac malformations, representing epigenetic memory, and adaption to hemodynamic alterations, which are jointly relevant for the disease course. METHODS AND RESULTS:We present the first analysis of genome-wide DNA methylation data obtained from myocardial biopsies of Tetralogy of Fallot (TOF) and ventricular septal defect patients. We defined stringent sets of differentially methylated regions between patients and controls, which are significantly enriched for genomic features like promoters, exons, and cardiac enhancers. For TOF, we linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. We validated and replicated the methylation of selected CpGs and performed functional assays. We identified a hypermethylated novel developmental CpG island in the promoter of SCO2 and demonstrate its functional impact. Moreover, we discovered methylation changes co-localized with novel, differential splicing events among sarcomeric genes as well as transcription factor binding sites. Finally, we demonstrated the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network. CONCLUSION:By interrogating DNA methylation and gene expression data, we identify two novel mechanism contributing to the phenotypic expression of CHDs: aberrant methylation of promoter CpG islands and methylation alterations leading to differential splicing.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Grunert M,Dorn C,Cui H,Dunkel I,Schulz K,Schoenhals S,Sun W,Berger F,Chen W,Sperling SRdoi
10.1093/cvr/cvw195subject
Has Abstractpub_date
2016-10-01 00:00:00pages
464-77issue
1eissn
0008-6363issn
1755-3245pii
cvw195journal_volume
112pub_type
杂志文章abstract:AIMS:We investigated the molecular mechanism of rapid-depolarization-induced atrial fibrosis. METHODS AND RESULTS:We used a direct atrial myocyte-fibroblast contact co-culture and a fibroblast-specific transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF) and procollagen type I α-1 (COL1A1) lu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvq322
更新日期:2011-03-01 00:00:00
abstract:AIMS:Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood. METHODS AND RESULTS:Here, we have identified naïve T cells in the aorta of wild-type and T-cell receptor transgenic mice and we demonstrate that naï...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvz102
更新日期:2020-02-01 00:00:00
abstract::Therapeutic neovascularization for cardiovascular ischemia is a promising avenue in spite of disappointing early clinical trial results. The concept of three different mechanisms of neovascularization has served to define potential therapeutic targets such as vascular remodeling and stem cell recruitment, but it is an...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2004.11.020
更新日期:2005-02-15 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::We have studied the responses to a brief interruption of a train of steady state beats, namely: (1) a single prolonged depolarisation within the train; (2) a single short interval within the train; (3) a single long interval within the train. These responses are predicted by a two compartment model of intracellular ca...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.10.1758
更新日期:1993-10-01 00:00:00
abstract::The effects of repeated (10 X), brief Ca2+-free perfusions (20 to 120 s) on myocardial contractility, coronary flow and release of cellular constituents of isolated rat heart were investigated. Ten successive Ca2+-deprivations of 20 or 40 s had no irreversible influences on cardiac performance. Ca2+-deprivations, howe...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/17.8.476
更新日期:1983-08-01 00:00:00
abstract:AIMS:Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvz136
更新日期:2019-12-01 00:00:00
abstract::Known viable allograft canine pulmonary valves were inserted in an isotopic position ensuring normal physiological function and simulating the clinical situation. Valves removed at periods up to eight weeks were assessed for viability using previously established criteria of tissue culture and protein and collagen syn...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/11.1.78
更新日期:1977-01-01 00:00:00
abstract::Platelet-dependent thrombus formation is a key event in the pathogenesis of acute myocardial infarction (AMI). Platelets mediate both thrombotic occlusion of the entire epicardial coronary artery and also accumulate in the microcirculation resulting in impairment of microcirculation and provoking myocardial ischemia d...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2003.11.036
更新日期:2004-02-15 00:00:00
abstract::The left ansa subclavia was stimulated at supramaximal intensity at a frequency of Hz in open-chest, anaesthetized dogs for periods of about 10 min. Arterial blood pressure, myocardial contractile force, and coronary sinus blood flow reached peak values after 1 or 2 min of stimulation, and then declined gradually thro...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/10.5.549
更新日期:1976-09-01 00:00:00
abstract:AIMS:The TRPV1, transient receptor potential vanilloid type 1, agonist capsaicin is considered to be beneficial for cardiovascular health because it dilates coronary arteries through an endothelial-dependent mechanism and may slow atheroma progression. However, recent reports indicate that high doses of capsaicin may c...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu152
更新日期:2014-09-01 00:00:00
abstract:OBJECTIVE:The aim was to investigate the influence of coronary occlusion on myocardial interstitial noradrenaline levels in the ischaemic and non-ischaemic regions, using the dialysis technique. METHODS:In nine anaesthetised cats, regional ischaemia was produced by occlusion of the left anterior descending coronary ar...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.5.817
更新日期:1993-05-01 00:00:00
abstract:AIMS:Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migr...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvv175
更新日期:2015-12-01 00:00:00
abstract:OBJECTIVES:To assess the functional effects of multipotent adult progenitor cells (MAPCs) transplanted in a rat model of chronic myocardial infarction. METHODS:Forty-four rats underwent coronary ligation and, 14 days later, were randomly allocated to receive in-scar injections (5 x 10(6) cells/150 microL) of green flu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2006.07.009
更新日期:2006-10-01 00:00:00
abstract::The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but rep...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvz013
更新日期:2019-04-15 00:00:00
abstract::Since data on velocity fields in the ascending aorta downstream of normal aortic valves in pigs have not yet been obtained velocity profiles were visualised using a hot film anemometer needle probe before and after total cardiopulmonary bypass and cold cardioplegic arrest. Furthermore, measurements were made during in...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/22.7.464
更新日期:1988-07-01 00:00:00
abstract::Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help...
journal_title:Cardiovascular research
pub_type: 杂志文章,meta分析
doi:10.1093/cvr/cvy145
更新日期:2018-09-01 00:00:00
abstract:OBJECTIVE:Inflammatory cells invade the fibrotic myocardium of spontaneously hypertensive rats at the same sites as where fibroblasts are produced. The role of these inflammatory cells in myocardial fibrogenesis was studied in the present work. METHODS:The production and distribution of proteins that may be implicated...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00
abstract:OBJECTIVE:Insulin seems to have vasodilator properties, but it is unclear if insulin in postprandial concentrations is a specific vasodilator of skeletal muscle resistance arterioles only or that various types of vessels are affected. The aim of the present study was to determine the direct effects and the time course ...
journal_title:Cardiovascular research
pub_type: 临床试验,杂志文章
doi:10.1016/s0008-6363(97)00035-7
更新日期:1997-04-01 00:00:00
abstract::Eicosanoids are important mediators of both physiological and pathophysiological responses of the microcirculation. These biologically active lipid mediators can be produced locally by the cellular elements within the microvasculature (endothelium, pericytes, smooth muscle cells) as well as interstitial cells (e.g. fi...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:
更新日期:1996-10-01 00:00:00
abstract::The structural nature of fibrillar collagen involved in the replacement fibrosis which accompanies discrete areas of cell necrosis remains uncertain, as does its influence on the diastolic and systolic stiffness of the intact myocardium. This study, using 15 micron diameter microsphere embolisation of the rat myocardi...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/23.8.655
更新日期:1989-08-01 00:00:00
abstract:OBJECTIVE:Increased cardiac collagen is seen in uninephrectomised rats made hypertensive by aldosterone infusion and high salt, with the possibility of a direct effect of aldosterone at the level of the cardiac fibroblast. The aim of this study was to examine the effects of aldosterone, glucocorticoids, and angiotensin...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.12.1863
更新日期:1994-12-01 00:00:00
abstract:AIMS:Doxorubicin (DOX) is a widely used and effective anti-cancer therapeutic. DOX treatment is associated with both acute and late onset cardiotoxicity, limiting its overall efficacy. Here, the impact of cardiomyocyte cell cycle activation was examined in a juvenile model featuring aspects of acute and late onset DOX ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvy273
更新日期:2019-04-15 00:00:00
abstract:OBJECTIVE:The objective of this study was to explore the relationship between low density lipoprotein (LDL) and dendritic cell (DC) activation, based upon the hypothesis that reactive oxygen species (ROS)-mediated modification of proteins that may be present in local DC microenvironments could be important as mediators...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00447-9
更新日期:2002-09-01 00:00:00
abstract::Mitochondria are often regarded as the powerhouse of the cell by generating the ultimate energy transfer molecule, ATP, which is required for a multitude of cellular processes. However, the role of mitochondria goes beyond their capacity to create molecular fuel, to include the generation of reactive oxygen species, t...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvs111
更新日期:2012-07-15 00:00:00
abstract:OBJECTIVE:Adenosine inhibits neutrophil adhesion and injury to isolated cardiac myocytes. In the present study, the contribution of selectin and CD18 interactions to neutrophil-myocyte adhesion and their sensitivity to adenosine were assessed. METHODS:Activated human neutrophils and canine myocytes were incubated with...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/0008-6363(96)00052-1
更新日期:1996-08-01 00:00:00
abstract:OBJECTIVE:Oxidized low-density lipoprotein (ox-LDL) increases superoxide anion (O(2)(-)) production by the endothelial nitric oxide (NO) synthase (eNOS). We assessed whether the uncoupling of eNOS was associated with alterations in eNOS phosphorylation and/or the assembly of the eNOS signaling complex. METHODS AND RES...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.11.003
更新日期:2005-03-01 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:AIMS:Vascular inflammation is a major atherogenic factor and Toll-like receptor (TLR) 2 ligands, including bacterial and serum lipoproteins, seem to be involved in atherogenesis. On this basis, we analysed the effect of lipoproteins and different lipid components on TLR2-dependent signalling. METHODS AND RESULTS:In TL...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn087
更新日期:2008-08-01 00:00:00
abstract:AIMS:Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing th...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvaa307
更新日期:2020-10-29 00:00:00