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 role of these AF GWAS-related genes in AF and their inter-relationship remain elusive. METHODS AND RESULTS:To get further insights into the molecular mechanisms driven by Pitx2, calcium handling and novel AF GWAS-associated gene expression were analysed in two distinct Pitx2 loss-of-function models with distinct basal electrophysiological defects; a novel Pitx2 conditional mouse line, Sox2CrePitx2, and our previously reported atrial-specific NppaCrePitx2 line. Molecular analyses of the left atrial appendage in NppaCrePitx2(+/-) and NppaCrePitx2(-/-) adult mice demonstrate that AF GWAS-associated genes such as Zfhx3, Kcnn3, and Wnt8a are severely impaired but not Cav1, Synpo2l, nor Prrx1. In addition, multiple calcium-handling genes such as Atp2a2, Casq2, and Plb are severely altered in atrial-specific NppaCrePitx2 mice in a dose-dependent manner. Functional assessment of calcium homeostasis further underscores these findings. In addition, multiple AF-related microRNAs are also impaired. In vitro over-expression of Wnt8, but not Zfhx3, impairs calcium handling and modulates microRNA expression signature identified in Pitx2 loss-of-function models. CONCLUSION:Our data demonstrate a dose-dependent relation between Pitx2 expression and the expression of AF susceptibility genes, calcium handling, and microRNAs and identify a complex regulatory network orchestrated by Pitx2 with large impact on atrial arrhythmogenesis susceptibility.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Lozano-Velasco E,Hernández-Torres F,Daimi H,Serra SA,Herraiz A,Hove-Madsen L,Aránega A,Franco Ddoi
10.1093/cvr/cvv207subject
Has Abstractpub_date
2016-01-01 00:00:00pages
55-66issue
1eissn
0008-6363issn
1755-3245pii
cvv207journal_volume
109pub_type
杂志文章abstract：:The isolated perfused heart has been used increasingly during the last decade as a model for identifying actions of drugs on ventricular fibrillation (VF) induced by myocardial ischaemia. In addition, it has been used to explore the mechanisms responsible for the initiation and maintenance of VF, the concept of endoge...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(98)00083-2
更新日期：1998-07-01 00:00:00
abstract：OBJECTIVE:Sphingosine 1-phosphate is a naturally occurring biologically active lysophospholipid. Recent studies suggested that sphingosine 1-phosphate is released into the blood flow from activated platelets upon stimulation to exert multiple biological phenomenon. The purpose of this study was to assess the effects of...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(00)00013-4
更新日期：2000-04-01 00:00:00
abstract：AIMS:Atherogenesis, evolution of plaque, and outcomes following endovascular intervention depend heavily on the unique vascular architecture of each individual. Patient-specific, multiscale models able to correlate changes in microscopic cellular responses with relevant macroscopic flow, and structural conditions may h...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvu124
更新日期：2014-07-01 00:00:00
abstract：:The efficacy of cardioprotective strategies can be quantified by myocardial salvage as an indicator of therapeutic benefit. Salvage is calculated as the difference between the area at risk (AAR) and the final infarct size (FIS). AAR has been quantified by angiographic assessment followed by quantification of FIS by bi...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvs081
更新日期：2012-05-01 00:00:00
abstract：OBJECTIVE:To evaluate the effects of aging on left ventricular (LV) geometry, collagen levels, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) abundance, and myocardial fibroblast function. METHODS:Young (3-month-old; n=28), middle-aged (MA; 15-month-old; n=17), and old (23-month-old; n...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2004.11.029
更新日期：2005-05-01 00:00:00
abstract：:Computation of indices of regional myocardial contractility such as the shortening, or the work done by or on a segment of myocardium in a single cardial cycle is tedious to perform manually, and complex interfacing and software is needed for digital computation. We describe the principles of an on-line, analogue devi...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/17.12.767
更新日期：1983-12-01 00:00:00
abstract：OBJECTIVE:To investigate the cellular mechanisms underlying global and regional LV dysfunction in the post-infarct (MI) remodeled rat hearts. METHODS:LV remodeling and function were quantified by echocardiography, morphometry, in vivo hemodynamics, and isolated perfused heart studies in 6 weeks post-MI and sham-operat...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(00)00160-7
更新日期：2000-10-01 00:00:00
abstract：OBJECTIVE:Persistent atrial fibrillation (AF) results in an impairment of atrial function. In order to elucidate the mechanism behind this phenomenon, we investigated the gene expression of proteins influencing calcium handling. METHODS:Right atrial appendages were obtained from eight patients with paroxysmal AF, ten ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00045-0
更新日期：1999-05-01 00:00:00
abstract：AIMS:Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function in endothelial homeostasis. We investigat...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvp365
更新日期：2010-03-01 00:00:00
abstract：:The effect on the microcirculation of long term administration of the alpha 1 blocker prazosin, which increases peripheral blood flow, was studied in skeletal muscles with differing metabolic profiles. Prazosin (50 mg.litre-1), given ad libitum for 5 weeks in the drinking water, resulted in an increase in capillarity ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/23.11.913
更新日期：1989-11-01 00:00:00
abstract：AIMS:Following a large myocardial infarction (MI), remaining viable muscle often undergoes pathological remodelling and progresses towards chronic heart failure. Mitochondria may also be affected by this process and, due to their functional importance, likely contribute to the progression of the disease. Aerobic interv...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvt080
更新日期：2013-07-01 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：AIMS:The mesenchymal cushions lining the early embryonic heart undergo complex remodelling to form the membranous ventricular septum as well as the atrioventricular and semilunar valves in later life. Disruption of this process underlies the most common congenital heart defects. Here, we identified a novel role for Sli...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvv040
更新日期：2015-04-01 00:00:00
abstract：:Angiotensin II has been implicated as an important factor in cardiac remodeling, particularly in the development of pathological left ventricular hypertrophy. It is generally assumed that angiotensin II is able to alter the phenotype of cardiac myocytes and fibroblasts, and several experiments have suggested that this...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(01)00448-5
更新日期：2002-02-01 00:00:00
abstract：OBJECTIVES:Early thrombolysis can reduce infarct size and enhance the long term recovery of contractile function after acute myocardial infarction. These benefits of early reperfusion may be confounded, however, by platelet mediated reocclusion after initial lysis, and "reperfusion injury" mediated by oxygen derived fr...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/27.6.925
更新日期：1993-06-01 00:00:00
abstract：OBJECTIVE:The aim was to validate echocardiographic assessment of acute changes of left ventricular stroke volume in normal rats. METHODS:By transthoracic use of a 7.5 MHz ultrasonic transducer, the left ventricular dimensions were determined before and during rapid atrial pacing and saline infusion in seven Wistar ra...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/26.8.765
更新日期：1992-08-01 00:00:00
abstract：:Having an apparently healthy, thriving infant fail to reach his/her first birthday is profoundly tragic. This tragedy is compounded when the infant's death is unexpected and unexplained, signed out as sudden infant death syndrome (SIDS). Despite impressive success and welcome reductions in these tragic deaths due in l...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2005.02.013
更新日期：2005-08-15 00:00:00
abstract：AIMS:Caveolae are membrane microdomains where important signalling pathways are assembled and molecular effects transduced. In this study, we hypothesized that shear stress-mediated vasodilation (SSD) of mouse small coronary arteries (MCA) is caveolae-dependent. METHODS AND RESULTS:MCA (80-150 μm) isolated from wild-t...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvt157
更新日期：2013-10-01 00:00:00
abstract：OBJECTIVE:This study was conducted to evaluate to what extent the ischemia-reperfusion injury resulting from the cardiopulmonary bypass (CPB) and aortic cross-clamping procedures during coronary artery bypass grafting (CABG) contributes to the systemic inflammatory response generally found in these patients. METHODS:S...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00403-4
更新日期：2000-03-01 00:00:00
abstract：STUDY OBJECTIVE:Protective effects of nipradilol, a newly synthesised vasodilating beta adrenoceptor antagonist, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine were determined by coronary arteriography and compared in vivo in pigs. DESIGN:Acetylc...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/24.12.1013
更新日期：1990-12-01 00:00:00
abstract：OBJECTIVE:Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), acts on the pituitary and the hypothalamus to stimulate the release of growth hormone (GH) and promotes appetite and adiposity. It has also been reported to increase myocardial contractility, induce vasodilation, and protect again...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2004.01.024
更新日期：2004-06-01 00:00:00
abstract：:The major limitation to antiarrhythmic drug therapy is the risk of arrhythmia promotion, or 'proarrhythmia.' This complication may be lethal, and greatly restricts the value of antiarrhythmic agents, particularly for arrhythmias without an intrinsic mortality risk, such as atrial fibrillation. In order for improved an...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(97)00293-9
更新日期：1998-03-01 00:00:00
abstract：AIMS:P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomer...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvu249
更新日期：2015-02-01 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：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：AIMS:The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGFβ-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via in...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvu184
更新日期：2014-10-01 00:00:00
abstract：:In acute myocardial infarction (MI), reactive oxygen species (ROS) are generated in the ischaemic myocardium especially after reperfusion. ROS directly injure the cell membrane and cause cell death. However, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumour necrosis factor-alpha (...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvn335
更新日期：2009-02-15 00:00:00
abstract：:To investigate cardiovascular changes in experimental acromegaly, a growth hormone-secreting tumour (MtT-W-15) was implanted in adult female rats. Somatic and tumour growth occurred steadily during the 8 week study period, as did an increase in serum growth hormone titre. Weight of left ventricle and right ventricle i...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/19.5.270
更新日期：1985-05-01 00:00:00
abstract：STUDY OBJECTIVE:The objectives were (a) to describe the effects of vasoactive drugs in normal rats upon cardiovascular function assessed by computing aortic haemodynamic power and input impedance, each separated into their component parts, and (b) to study the relationship between left ventricular pulsatile power outpu...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/25.11.923
更新日期：1991-11-01 00:00:00
abstract：:Ischemia-reperfusion of the heart and other organs results in the accumulation of unesterified arachidonic acid (AA) via the action of membrane-bound phospholipases, primarily phospholipase A2. AA can be metabolized by the classical cyclooxygenase (COX) and lipoxygenase (LOX) pathways to well-characterized metabolites...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2005.06.007
更新日期：2005-10-01 00:00:00
