Abstract:
AIMS:Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and β2AR and ErbB2 complex in brain and heart, we hypothesized that β-adrenergic receptors (AR) modulate ErbB2 signalling status. METHODS AND RESULTS:ErbB2 transfection of HEK293 cells up-regulates β2AR, and β2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2(tg)) mice have amplified response to selective β2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with β2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that β2ARs levels are markedly increased in ErbB2(tg) myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with β1- and β2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either β1- or β2-AR antagonist did not completely prevent isoproterenol-induced ErbB2 expression. Furthermore, inhibition of ErbB2 kinase predisposed mice hearts to injury from chronic isoproterenol treatment while significantly reducing isoproterenol-induced pAKT and pERK levels, suggesting ErbB2's role in transactivation in the heart. CONCLUSION:Our studies show that myocardial ErbB2 and βAR signalling are linked in a feedback loop with βAR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating β2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of β-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Sysa-Shah P,Tocchetti CG,Gupta M,Rainer PP,Shen X,Kang BH,Belmonte F,Li J,Xu Y,Guo X,Bedja D,Gao WD,Paolocci N,Rath R,Sawyer DB,Naga Prasad SV,Gabrielson Kdoi
10.1093/cvr/cvv274subject
Has Abstractpub_date
2016-03-01 00:00:00pages
358-73issue
3eissn
0008-6363issn
1755-3245pii
cvv274journal_volume
109pub_type
杂志文章abstract::Stroke, ischaemic stroke and subtypes of ischaemic stroke display substantial heritability. When compared with related vascular conditions, the number of established risk loci reaching genome-wide significance for association with stroke is still in the lower range, particularly for aetiological stroke subtypes such a...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvy068
更新日期:2018-07-15 00:00:00
abstract:Aims:Endothelial hyperpermeability exacerbates multiple organ damage during inflammation or infection. The endothelial glycocalyx, a protective matrix covering the luminal surface of endothelial cells (ECs), undergoes enzymatic shedding during inflammation, contributing to barrier hyperpermeability. A disintegrin and m...
journal_title:Cardiovascular research
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doi:10.1093/cvr/cvy167
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abstract::Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-...
journal_title:Cardiovascular research
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doi:10.1093/cvr/cvab008
更新日期:2021-01-23 00:00:00
abstract:AIMS:Hypertension is a risk factor for atherothrombotic vascular events. Angiotensin II (Ang II), one of the main vasoactive hormones of the renin-angiotensin system, has been associated with the development and progression of atherosclerosis. However, it is not fully known how Ang II contributes to lipid-enriched athe...
journal_title:Cardiovascular research
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doi:10.1093/cvr/cvn043
更新日期:2008-06-01 00:00:00
abstract:OBJECTIVE:We determine if action potential duration (APD) shortening and cardioprotection are separable phenomena in ATP-sensitive potassium channel (KATP) openers which protect ischemic myocardium via a glyburide-reversible mechanism. METHODS:We determined the effect of the weakly vasodilating KATP opener, BMS-180448...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract:OBJECTIVE:Angiotensin II (ANG II) has recently been reported to increase inotropy in adult rabbit myocytes by a mechanism of alkalinization and consequent increased myofilament sensitivity to calcium. Accordingly, we tested the hypothesis that ANG II would have a greater inotropic effect during ischemic conditions than...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00185-x
更新日期:1997-01-01 00:00:00
abstract::Systemic haemodynamics and regional myocardial blood flow responses to hypertonic mannitol were studied in 10 conscious and 23 anaesthetized dogs. Mannitol infusion significantly increased regional myocardial blood flow in the conscious, intact dogs. Mannitol increased total coronary flow 20% in anasethetized animals ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/9.1.47
更新日期:1975-01-01 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
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00268-4
更新日期:1997-03-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 临床试验,杂志文章
doi:10.1016/s0008-6363(01)00325-x
更新日期:2001-09-01 00:00:00
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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:OBJECTIVE:Chlamydia pneumoniae infection has been associated with atherosclerosis, although the mechanisms by which C. pneumoniae contribute to atherogenesis remain unclear. Altered production of nitric oxide, a known bactericidal and anti-inflammatory agent, represents one possible mechanistic link. To examine this is...
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pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00389-4
更新日期:2003-10-15 00:00:00
abstract::A recently developed highly sensitive radioimmunoassay method for detecting plasma kinin was used to re-evaluate the results of previous studies, in which plasma kinin had been measured with a bioassay method. To clarify the mechanism of plasma kinin release in global myocardial ischaemia the left main coronary artery...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/21.6.428
更新日期:1987-06-01 00:00:00
abstract::The heart contains not only cardiomyocytes but also other cell types such as endothelial cells and fibroblasts. Functional crosstalk among these cell types is important for normal cardiac function and is also involved in disease pathophysiology. Recent data indicate that redox signalling within and between endothelial...
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pub_type: 杂志文章,评审
doi:10.1093/cvr/cvu050
更新日期:2014-05-01 00:00:00
abstract::The therapeutic potential of Hedgehog (Hh) signalling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signalling in vascular biology remain poorly understood. AIMS:The purpose of the present paper is to clarify some conflicting literature...
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doi:10.1093/cvr/cvaa285
更新日期:2020-10-16 00:00:00
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doi:10.1016/j.cardiores.2005.09.011
更新日期:2006-01-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2007.04.006
更新日期:2007-08-01 00:00:00
abstract:OBJECTIVE:Defects in myocardial mitochondrial structure and function have been associated with heart failure in humans and animal models. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure. We tested the hypothesis that defects in...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.10.025
更新日期:2005-02-01 00:00:00
abstract::The response of a simple systolic time interval, the interval between the Q wave and the onset of the aortic blood pressure pulse (the QA interval), to changes in cardiac contractility, cardiac loading, and heart rate was evaluated in anaesthetised open chest dogs. The QA interval was found to be sensitive to increase...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.6.444
更新日期:1986-06-01 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
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doi:10.1093/cvr/25.7.603
更新日期:1991-07-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/22.8.537
更新日期:1988-08-01 00:00:00
abstract:AIMS:Moderate wine consumption is associated with a significant reduction of cardiovascular mortality. The molecular basis of this phenomenon remains unknown. Platelet-derived growth factor (PDGF) is an important contributor to atherogenesis. We investigated the effects of selected red and white wines on PDGF receptor ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn340
更新日期:2009-03-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/cvn054
更新日期:2008-07-15 00:00:00
abstract:OBJECTIVE:The aim was to determine if either heparin or N-acetylheparin could reduce the extent of myocardial injury resulting from 90 min of coronary artery occlusion and 6 h of reperfusion in the anaesthetised dog. METHODS:Heparin or N-acetylheparin was given in three repeated intravenous doses of 2 mg.kg-1. Drug or...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::An oscillatory current (Ios) can be recorded after depolarising clamps of a given amplitude and duration. To determine whether Ios depends on other currents activated during the clamp, the Ios was investigated in the absence and in the presence of 4-aminopyridine (4-AP) and cesium (Cs). The following results were obta...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/16.11.637
更新日期:1982-11-01 00:00:00
abstract::Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and the availability of percutaneous or surgical revascularization procedures significantly improves survival. However, both strategies are daunted by complications which limit long-term effectiveness. In-stent...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvz214
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:10.1016/s0008-6363(99)00103-0
更新日期:1999-09-01 00:00:00
abstract::Postextrasystolic potentiation was studied by means of a catheter-tip manometer in patients with and without cardiomyopathy. The results imply that the enhancement of the left ventricular contraction is increased in patients with cardiomyopathy. ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/9.3.336
更新日期:1975-05-01 00:00:00