Abstract:
:Congenital heart defects affect almost 1% of human newborns. Recently, mutations in Notch ligands and receptors have been found to cause a variety of heart defects in rodents and humans. However, the molecular effects downstream of Notch are still poorly understood. Here we report that combined inactivation of Hey1 and HeyL, two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal defects and dysplastic atrioventricular and pulmonary valves. These defects lead to congestive cardiac failure with high lethality. We found both genes to be coexpressed with Notch1, Notch2 and the Notch ligand Jagged1 in the endocardium of the atrioventricular canal, representing the primary source of mesenchymal cells forming membraneous septum and valves. Atrioventricular explants from Hey1/HeyL deficient mice exhibited impaired epithelial to mesenchymal transition. Although epithelial to mesenchymal transition was initiated regularly, full transformation into mesenchymal cells failed. This was accompanied by reduced levels of matrix metalloproteinase-2 expression and reduced cell density in endocardial cushions in vivo. We further show that loss of Hey2 leads to very similar deficiencies, whereas a Notch1 null mutation completely abolishes epithelial to mesenchymal transition. Thus, the Hey gene family shows overlap in controlling Notch induced endocardial epithelial to mesenchymal transition, a process critical for valve and septum formation.
journal_name
Circ Resjournal_title
Circulation researchauthors
Fischer A,Steidl C,Wagner TU,Lang E,Jakob PM,Friedl P,Knobeloch KP,Gessler Mdoi
10.1161/01.RES.0000260913.95642.3bsubject
Has Abstractpub_date
2007-03-30 00:00:00pages
856-63issue
6eissn
0009-7330issn
1524-4571pii
01.RES.0000260913.95642.3bjournal_volume
100pub_type
杂志文章abstract:RATIONALE:Plakophilin-2 (PKP2) is an essential component of the cardiac desmosome. Recent data show that it interacts with other molecules of the intercalated disc. Separate studies show preferential localization of the voltage-gated sodium channel (Na(V)1.5) to this region. OBJECTIVE:To establish the association of P...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.201418
更新日期:2009-09-11 00:00:00
abstract::To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.59.3.256
更新日期:1986-09-01 00:00:00
abstract::To assess whether coronary spasm affects the progression of atherosclerosis and results in evolution of myocardial infarction, the role of coronary spasm on the fine structure of conduit coronary arteries was studied morphologically. Göttingen miniature pigs were fed a semisynthetic diet containing 2% cholesterol and ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.2.272
更新日期:1989-08-01 00:00:00
abstract::This paper describes use of the Karhunen-Loeve expansion to identify and reduce temporal redundancy in electrocardiographic body surface potential maps (192 body surface leads recorded simultaneously at 1 kHz/channel for approximately 600 msec). Temporal data compression of about 20 to 1 was obtained with accurate rep...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.1.197
更新日期:1981-07-01 00:00:00
abstract::The objective of this study was to elucidate the mechanisms associated with the reciprocal relation between magnesium and calcium on vascular smooth muscle tone in bovine pulmonary artery and vein. Rapid removal of magnesium from Krebs-bicarbonate medium used to bathe isolated rings of precontracted artery or vein cau...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.2.355
更新日期:1990-02-01 00:00:00
abstract::The 2-amino-3-benzoylthiophene derivative PD 81,723 is an allosteric enhancer of agonist binding to brain A1 adenosine receptors. One aim of this study was to characterize and contrast the effects of PD 81,723 on the A1 receptor-mediated negative dromotropic and A2a receptor-mediated vasodilatory actions of adenosine ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.75.6.961
更新日期:1994-12-01 00:00:00
abstract::Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000107196.21335.2B
更新日期:2004-01-09 00:00:00
abstract::To study the effects of stretch on the function of rat left atrium, we recorded contraction force, calcium transients, and intracellular action potentials (APs) during stretch manipulations. The stretch of the atrium was controlled by intra-atrial pressure. The Frank-Starling behavior of the atrium was manifested as a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.83.11.1165
更新日期:1998-11-30 00:00:00
abstract::The kinetic attributes of the afferent arteriole myogenic response were investigated using the in vitro perfused hydronephrotic rat kidney. Equations describing the time course for pressure-dependent vasoconstriction and vasodilation, and steady-state changes in diameter were combined to develop a mathematical model o...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000024262.11534.18
更新日期:2002-06-28 00:00:00
abstract::Purkinje cells contain sarcoplasmic reticulum (SR) directly under the surface membrane, are devoid of t-tubuli, and are packed with myofibrils surrounded by central SR. Several studies have reported that electrical excitation induces a biphasic Ca(2+) transient in Purkinje fiber bundles. We determined the nature of th...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.4.448
更新日期:2000-03-03 00:00:00
abstract::Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac S...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.118.313261
更新日期:2018-08-03 00:00:00
abstract::Triadin 1 (TRD) is an integral membrane protein that associates with the ryanodine receptor (RyR2), calsequestrin (CASQ2) and junctin to form a macromolecular Ca signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). To define the functional role of TRD, we examined the effects of adenoviral-mediated...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000160609.98948.25
更新日期:2005-04-01 00:00:00
abstract:RATIONALE:Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies ha...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.112.270132
更新日期:2012-09-28 00:00:00
abstract::Shear stress-induced activation of endothelial ion channels, one of the earliest responses to flow, is implicated in mechano-signal transduction that results in the regulation of vascular tone. The effects of laminar flow on endothelial membrane potential were studied in vitro using both fluorescent potentiometric dye...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.85.9.820
更新日期:1999-10-29 00:00:00
abstract:RATIONALE:Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIV...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.300350
更新日期:2013-03-15 00:00:00
abstract::Protein kinase C (PKC) is a key mediator of many diverse physiological and pathological responses. Although little is known about the specific in vivo roles of the various cardiac PKC isozymes, activation-induced translocation of PKC is believed to be the primary determinant of isozyme-specific functions. Recently, we...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.11.1173
更新日期:2000-06-09 00:00:00
abstract::Aldosterone is associated with the pathogenesis and progression of left ventricular hypertrophy and heart failure, independent of its relation with arterial blood pressure. However, little information exists about the possible influence of this mineralocorticoisteroid on cardiomyocyte electrical activity. The present ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.85.12.1139
更新日期:1999-12-03 00:00:00
abstract::Inflammation is a condition that underscores many cardiovascular pathologies including endothelial dysfunction, but no link is yet established between the vascular pathology of the metabolic syndrome with a particular inflammatory cytokine. We hypothesized that impairments in coronary endothelial function in the obese...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000229685.37402.80
更新日期:2006-07-07 00:00:00
abstract::Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with bet...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.118.313155
更新日期:2019-02-01 00:00:00
abstract:RATIONALE:Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.307017
更新日期:2016-01-22 00:00:00
abstract::Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.85.5.403
更新日期:1999-09-03 00:00:00
abstract::Changes in cardiac filling pressure (central venous pressure) were measured following carotid occlusion and infusions of catecholamines in awake dogs while cardiac output was held constant. After carotid occlusion in dogs with vagi blocked, central venous pressure increased about 0.8 mm Hg (an estimated decrease in va...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.55.4.440
更新日期:1984-10-01 00:00:00
abstract::The identification of nitric oxide ((*)NO) as an endogenously produced free radical mediator of endothelial-dependent relaxation and host defense has fundamentally changed concepts of cell signal transduction. Ligand-receptor oriented paradigms of cell signaling were originally centered on the concept of a high affini...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.109.202077
更新日期:2009-09-11 00:00:00
abstract:RATIONALE:MicroRNAs modestly suppress their direct mRNA targets, and these direct effects are amplified by modulation of gene transcription pathways. Consequently, indirect mRNA modulatory effects of microRNAs to increase or decrease mRNAs greatly outnumber direct target suppressions. Because microRNAs are products of ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.300975
更新日期:2013-06-21 00:00:00
abstract:RATIONALE:Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation. OBJECTIVE:To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.302089
更新日期:2014-01-03 00:00:00
abstract:RATIONALE:Innate and adaptive immune responses alter numerous homeostatic processes that are controlled by nuclear hormone receptors. NR4A1 is a nuclear receptor that is induced in vascular pathologies, where it mediates protection. OBJECTIVE:The underlying mechanisms that regulate the activity of NR4A1 during vascula...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.258814
更新日期:2012-04-13 00:00:00
abstract::To determine the mechanical factors affecting regional segmental motion after acute coronary occlusion, we studied seven conscious dogs, instrumented with sonomicrometers. Loading conditions were changed by the withdrawal of 500 ml of blood and the transfusion of 800 ml of blood. To express segmental motion, percent s...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.58.2.209
更新日期:1986-02-01 00:00:00
abstract::Electrical propagation in the normal heart occurs via intercellular transfer of current at gap junctions. Alterations in intercellular coupling in the diseased heart are critical in the pathogenesis of reentrant ventricular arrhythmias. Until recently only a single gap junction protein was known to couple cardiac myoc...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.2.438
更新日期:1992-02-01 00:00:00
abstract::Compared with the adult, neonatal heart muscle is less sensitive to deactivation by acidic pH. We hypothesized that expression of slow skeletal troponin I (ssTnI), the embryonic isoform, in adult heart would help maintain left ventricular (LV) systolic function during respiratory hypercapnia. We assessed LV function b...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000173849.68636.1e
更新日期:2005-07-08 00:00:00
abstract::Mechanical forces participate in morphogenesis from the level of individual cells to whole organism patterning. This article reviews recent research that has identified specific roles for mechanical forces in important developmental events. One well defined example is that dynein-driven cilia create fluid flow that de...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.108.175331
更新日期:2008-08-01 00:00:00