Abstract:
Aims:Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results:Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions:Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Grund A,Szaroszyk M,Döppner JK,Malek Mohammadi M,Kattih B,Korf-Klingebiel M,Gigina A,Scherr M,Kensah G,Jara-Avaca M,Gruh I,Martin U,Wollert KC,Gohla A,Katus HA,Müller OJ,Bauersachs J,Heineke Jdoi
10.1093/cvr/cvy154subject
Has Abstractpub_date
2019-01-01 00:00:00pages
71-82issue
1eissn
0008-6363issn
1755-3245pii
5040493journal_volume
115pub_type
杂志文章abstract:AIM:Clinical use of amiodarone is associated with occasional development of torsade de pointes (TdP). However, preclinical models have failed to demonstrate the proarrhythmic potential of amiodarone. The objective of this study was to reveal and explain the pro- and anti-arrhythmic effects of acute exposure to amiodaro...
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
abstract:OBJECTIVE:In human heart failure beta-adrenergic-mediated protein kinase A (PKA) activity is down-regulated, while protein kinase C (PKC) activity is up-regulated. PKC-mediated myofilament protein phosphorylation might be detrimental for contractile function in cardiomyopathy. This study was designed to reveal the effe...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.11.021
更新日期:2006-03-01 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:OBJECTIVE:The aim was to investigate the effect of increased left ventricular filling pressure on the pulmonary vein flow (PVQ) pattern. METHODS:Pulmonary vein flow was recorded using an ultrasonic transit time flow meter in six anaesthetised dogs. Mean left atrial pressure was increased by stepwise volume loading fro...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.3.411
更新日期:1993-03-01 00:00:00
abstract:AIMS:Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPARgam...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn308
更新日期:2009-02-01 00:00:00
abstract::An investigation of changes in the Mg2+ -dependent, Na+ -K+ -stimulated sarcolemmal ATPase and of intracellular electrolytes in the left failing heart due to pressure overload (aortic banding) was carried out in dogs. There was no change in the sarcolemmal Mg2+ -ATPase of the left or right ventricle for the whole dura...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.2.95
更新日期:1979-02-01 00:00:00
abstract::The effect of adding fibrinolytic to penicillin therapy in experimentally induced streptococcal bacterial endocarditis has been studied in the rabbit. In 9 day old infected lesions, the vegetations could be substantially reduced in size after a 3 day course of intravenous streptokinase. Quantitative microbiological te...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/14.8.482
更新日期:1980-08-01 00:00:00
abstract:OBJECTIVE:The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension. METHODS:To this...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00318-8
更新日期:2002-07-01 00:00:00
abstract:OBJECTIVE:The present study investigated whether activation of phosphatidylinositol 3-kinase (PI3-kinase) is involved in the stimulation of hypertrophic growth of adult ventricular cardiomyocytes under alpha- or beta-adrenoceptor stimulation. METHODS:Adult ventricular rat cardiomyocytes were used either directly after...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00171-0
更新日期:1998-10-01 00:00:00
abstract::Muscle tissue in atrioventricular (A-V) cardiac valve leaflets was studied in 35 human hearts and was found to be more prominent in the anterior leaflet of the mitral (MAL) than in the other valve leaflets. From serial sectioning and wax model reconstruction, the anatomic arrangement of the muscle in the MAL indicates...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/12.11.675
更新日期:1978-11-01 00:00:00
abstract::Vascular endothelial growth factors (VEGFs) are key regulators of permeability. The principal evidence behind how they increase vascular permeability in vivo and in vitro and the consequences of that increase are addressed here. Detailed analysis of the published literature has shown that in vivo and in vitro VEGF-med...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvq105
更新日期:2010-07-15 00:00:00
abstract:AIMS:The aim of this study was to explore meprinα-mediated transactivation of the epidermal growth factor receptor (EGFR) and reactive oxygen species (ROS) production in macrophages. METHODS AND RESULTS:Accelerated atherosclerotic lesions were established by administration of a high-fat diet in apolipoprotein E-defici...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvs369
更新日期:2013-03-01 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
abstract::A mathematical formulation of the blood flow behaviour through a capillaron model is described. The formulation is applied to the analysis of post-occlusion (reactive) hyperaemia and autoregulation. ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/10.1.13
更新日期:1976-01-01 00:00:00
abstract:OBJECTIVES:Coronary microvascular endothelial cells (CMVEs) can modulate the contractile performance of the adjacent myocardium by the release of agents such as nitric oxide (NO). Most previous studies using CMVEs have been done in situ, in the intact organ. We set out to study possible differences in NO synthase (NOS)...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00336-8
更新日期:1999-06-01 00:00:00
abstract::Cardiovascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(02)00828-3
更新日期:2003-10-15 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:Experimental evidence suggests that modulation of myocardial substrate metabolism can markedly affect the progression of chronic heart failure (HF). We tested whether the inhibition of carnitine palmitoyl transferase-I (CPT-I), the enzyme regulating mitochondrial fatty acid oxidation, slows left ventricular r...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.02.004
更新日期:2005-06-01 00:00:00
abstract:AIMS:The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with f...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvw233
更新日期:2017-01-01 00:00:00
abstract::The effect of axial rotation on flow through and pressure gradient across saphenous vein segments was studied using 15 cadaver long saphenous veins. A significant reduction in flow occurred at a mean rotation of 25 degrees/cm and a significant increase in head loss across the segments occurred at a mean rotation of 23...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/9.4.538
更新日期:1975-07-01 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:OBJECTIVE:Ischaemic preconditioning may be mediated by oxygen free radicals generated during preconditioning. Conflicting results have been reported regarding the effect of superoxide dismutase (SOD) in attenuating the cardioprotective effect of preconditioning. The aim of the study was to reconcile this conflict by ex...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.7.980
更新日期:1994-07-01 00:00:00
abstract:OBJECTIVE:Decay kinetics of the voltage-gated L-type Ca(2+) current (I(CaL)) control the magnitude of Ca(2+) influx during the cardiac action potential. We investigated the influence of changes in diastolic membrane potential on I(CaL) decay kinetics in cardiac cells. METHODS:Cells were isolated enzymatically from rat...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(00)00107-3
更新日期:2000-08-01 00:00:00
abstract:AIMS:Atherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque hemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and ATF1. The anti-diabetic drug metformin may also activate AMPK-dependent signalling. HYPOTHESIS:Metformin systematically indu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvaa171
更新日期:2020-07-15 00:00:00
abstract:OBJECTIVE:Calcitonin gene related peptide (CGRP) is a potent vasodilator found in sensory nerve endings in coronary arteries. The effect of intravenous CGRP on myocardial ischaemia, cardiovascular haemodynamics, and epicardial coronary artery stenoses was studied in patients with angina to investigate the possible role...
journal_title:Cardiovascular research
pub_type: 临床试验,杂志文章
doi:10.1093/cvr/27.8.1477
更新日期:1993-08-01 00:00:00
abstract::Cardiomyocyte death secondary to transient ischaemia occurs mainly during the first minutes of reperfusion in the form of contraction band necrosis. Research on the mechanisms leading to sarcolemmal rupture and necrosis during initial reperfusion identified several promising pharmacological targets directed either to ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvp109
更新日期:2009-07-15 00:00:00
abstract:OBJECTIVE:We investigated the influence of experimental hyperlipidemia on the formation of cardiac NO, superoxide, and peroxynitrite (ONOO(-)) in rat hearts. METHODS:Wistar rats were fed 2% cholesterol-enriched diet or normal diet for 8 weeks. Separate groups of normal and hyperlipidemic rats were injected twice intra...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00330-4
更新日期:2003-06-01 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::Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.10.721
更新日期:1986-10-01 00:00:00
abstract::The mechanisms whereby glucose reduces fatty acid-induced release of enzyme from the coronary-ligated isolated perfused working rat heart are investigated. Alterations in the tissue contents of ATP, phosphocreatine, or glycogen could be excluded as possible mechanisms for the beneficial effect of glucose in this syst...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.12.693
更新日期:1979-12-01 00:00:00