Abstract:
AIMS:Germ-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRAS(G12D) expression in the heart. METHODS AND RESULTS:To generate mice with endogenous cardiomyocyte-specific KRAS(G12D) expression (cKRAS(G12D) mice), we bred mice with a Cre-inducible allele expressing KRAS(G12D) from its endogenous promoter (Kras2(LSL)) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRAS(G12D) mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRAS(G12D) mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart. CONCLUSION:Mice with cardiomyocyte-specific KRAS(G12D) expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Dalin MG,Zou Z,Scharin-Täng M,Safari R,Karlsson C,Bergo MOdoi
10.1093/cvr/cvt260subject
Has Abstractpub_date
2014-02-01 00:00:00pages
229-35issue
2eissn
0008-6363issn
1755-3245pii
cvt260journal_volume
101pub_type
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt126
更新日期:2013-08-01 00:00:00
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journal_title:Cardiovascular research
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更新日期:2005-03-01 00:00:00
abstract::Congenital coronary artery anomalies are of major significance in clinical cardiology and cardiac surgery due to their association with myocardial ischaemia and sudden death. Such anomalies are detectable by imaging modalities and, according to various definitions, their prevalence ranges from 0.21 to 5.79%. This cons...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
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更新日期:2016-02-01 00:00:00
abstract:OBJECTIVE:There is accumulating evidence that oestrogen replacement therapy protects against the development of coronary atherosclerosis and myocardial infarction in postmenopausal women. The mechanism of this protective effect is uncertain. The aim of this study was to measure the effects of 17 beta-oestradiol on huma...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.11.1939
更新日期:1993-11-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1016/s0008-6363(97)00242-3
更新日期:1998-03-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvz145
更新日期:2020-03-01 00:00:00
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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
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvm069
更新日期:2008-02-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/cvr037
更新日期:2011-07-15 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.03.011
更新日期:2005-07-01 00:00:00
abstract:AIMS:Sulfur dioxide (SO₂) is an air pollutant that impedes neonatal development and induces adverse cardiorespiratory health effects, including tachycardia. Here, an animal model was developed that enabled characterization of (i) in vivo alterations in heart rate and (ii) altered activity in brainstem neurons that cont...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt057
更新日期:2013-07-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(00)00187-5
更新日期:2000-12-01 00:00:00
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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:Junctin is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum, which forms a quaternary complex with the ryanodine receptor (Ca(2+) release channel), triadin, and calsequestrin. METHODS:To better understand the role of junctin in excitation-contraction coupling in the heart, we genera...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00432-2
更新日期:2003-08-01 00:00:00
abstract:AIMS:The cAMP-dependent protein kinase (PKA) mediates β-adrenoceptor (β-AR) regulation of cardiac contraction and gene expression. Whereas PKA activity is well characterized in various subcellular compartments of adult cardiomyocytes, its regulation in the nucleus remains largely unknown. The aim of the present study w...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu029
更新日期:2014-04-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00270-3
更新日期:1999-04-01 00:00:00
abstract:OBJECTIVE:The aim was to further characterise an experimental model of preconditioning of isolated rabbit cardiomyocytes and to determine the role of adenosine receptor subtypes in initiation of the protective response. METHODS:Isolated myocytes were subjected to 5 min preincubation in the presence or absence of gluco...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.7.1049
更新日期:1994-07-01 00:00:00
abstract::Integrative genomics studies have greatly advanced our understanding of cardiovascular pathophysiology over the last decade. Here, we highlight the strengths and challenges of this cutting-edge approach and provide examples where novel insights have arisen through the integration of multi-level genomic information and...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvs303
更新日期:2013-03-15 00:00:00
abstract:AIMS:Smad7 plays a negative regulatory role in many inflammatory diseases, but its effect on hypertensive disease remains unknown. The present study tested the hypothesis that overexpression of Smad7 may have therapeutic potential for angiotensin II (Ang II)-mediated hypertensive cardiac remodelling. METHODS AND RESUL...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt151
更新日期:2013-09-01 00:00:00
abstract::The effects on an acute myocardial infarction of equipotent hypotensive doses of nitroglycerin and dipyridamole were studied using the thermographic technique in open-chest dogs. Nitroglycerin did not reduce the cool ischaemic area in any of the nine dogs studied. In six of the dogs, in which the ischaemic region coul...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.5.281
更新日期:1979-05-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.7.1036
更新日期:1994-07-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.4.585
更新日期:1993-04-01 00:00:00
abstract:AIMS:The role of endothelial nitric oxide synthase (eNOS)/NO signalling is well documented in late ischaemic preconditioning (IPC); however, the role of eNOS and its activation in early IPC remains controversial. This study investigates the role of eNOS in early IPC and the signalling pathways and molecular interaction...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvs287
更新日期:2013-01-01 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
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.9.839
更新日期:1992-09-01 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::A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvp170
更新日期:2009-07-15 00:00:00
abstract:AIMS:GATA4 is a transcription factor that is up-regulated during cardiac hypertrophy and plays a fundamental role in myocyte growth and survival. In this study, we investigate the transcriptional vs. post-transcriptional mechanisms that are involved in regulating GATA4 in the heart during neonatal and pressure overload...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvs001
更新日期:2012-03-15 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvm022
更新日期:2008-01-01 00:00:00
abstract:OBJECTIVE:Previous studies showed that treatment of hearts with nisoldipine improves recovery of cardiac function following ischaemia, improves reperfusion, and reduces the constrictor sensitivity to endothelin. The aim of the present study was to assess the reduction in vasodilator responses that occurs following isch...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.6.990
更新日期:1993-06-01 00:00:00