Abstract：
AIMS:To define the molecular mechanisms of cardiotoxicity induced by Sunitinib and to identify the role of biological sex in modulating toxicity. METHODS AND RESULTS:Exposure of isolated cardiomyocytes to plasma-relevant concentrations of Sunitinib and other tyrosine kinase inhibitors produces a broad spectrum of abnormalities and cell death via apoptosis downstream of sexually dimorphic kinase inhibition. Phosphorylation of protein kinase C and phospholipase γ abrogates these effects for most tyrosine kinase inhibitors tested. Female sex and estradiol cause increased cardiotoxicity, which is mediated by reduced expression of a drug efflux transporter and a metabolic enzyme. Female but not male mice exposed to a 28-day course of oral Sunitinib exhibit similar abnormalities as well as functional deficits and their hearts exhibit differential expression of genes responsible for transport and metabolism of Sunitinib. CONCLUSION:We identify the specific pathways affected by tyrosine kinase inhibitors in mammalian cardiomyocytes, interactions with biological sex, and a role for oestrogen in modulating drug efflux and metabolism. These findings represent a critical step toward reducing the incidence of cardiotoxicity with tyrosine kinase inhibitor chemotherapeutics.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Harvey PA,Leinwand LAdoi
10.1093/cvr/cvv152subject
Has Abstractpub_date
2015-07-01 00:00:00pages
66-77issue
1eissn
0008-6363issn
1755-3245pii
cvv152journal_volume
107pub_type
杂志文章abstract：:To provide further evidence that the veratrum alkaloids' mechanical, positive inotropic effect and not their chemical depolarising action predominates in initiating the left ventricular mechanoreceptor (including the Bezold) reflex the effect of intracoronary KCl, a chemical depolarising agent like the veratrum alkalo...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/18.8.514
更新日期：1984-08-01 00:00:00
abstract：OBJECTIVES:To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM). METHODS:We studied 19 conscious, instrumented dogs with pacing-induced D...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(01)00490-4
更新日期：2002-02-01 00:00:00
abstract：OBJECTIVE:Vascular smooth muscle cell (VSMC) de-differentiation is a prerequisite for migration from the tunica media to the intima after vascular injury. Integrin cell adhesion molecules participate in VSMC phenotype modulation. Alpha 8 beta 1 integrin is a differentiation marker of VSMCs and its knockdown heightens m...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2006.03.003
更新日期：2006-07-01 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
abstract：OBJECTIVE:Migration and proliferation of arterial smooth muscle cells are critical responses during restenosis after balloon angioplasty. We investigated the changes in the expression of Ca(2+) channels and dystrophin, two determinants of contraction, after balloon injury of rat aortas. METHODS:Proliferation and migra...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(00)00210-8
更新日期：2001-01-01 00:00:00
abstract：OBJECTIVE:The aim of this study was to determine whether chronic beta-adrenergic receptor (beta-AR) stimulation induces proliferation of human cardiac fibroblasts and to investigate the mechanism(s) involved. METHODS AND RESULTS:In vitro cultures of human cardiac fibroblasts were established from biopsies of right atr...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(02)00729-0
更新日期：2003-03-01 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：OBJECTIVE:The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS:Nine healthy volunteers received intra-arterial infusions of angiotensin II, ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/28.5.663
更新日期：1994-05-01 00:00:00
abstract：OBJECTIVE:To investigate the possible mechanisms of the antiatherosclerotic effects of the angiotensin-converting enzyme (ACE) inhibitor, fosinopril, in apolipoprotein (apo) E deficient mice. METHODS:Apo E deficient (E0) mice at the age of 8 weeks received either placebo or a high dose (25 mg/kg/d) of fosinopril suppl...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00239-4
更新日期：1999-12-01 00:00:00
abstract：:Controversy exists as to whether the diabetic heart is more or less sensitive to ischemic injury. Although a considerable number of experimental studies have directly determined the effects of ischemia on the diabetic heart, there is still no general agreement as to whether metabolic changes within the myocardium cont...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(97)00037-0
更新日期：1997-04-01 00:00:00
abstract：OBJECTIVE:Air bubbles entering the coronary artery may have harmful effects on cardiac function. From the physical point of view it is the relatively high surface tension of the blood-air interface which causes bubbles to trap in small vessels. The aim of the present study was to reduce depression of myocardial functio...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(97)00063-1
更新日期：1997-06-01 00:00:00
abstract：:The theory related to the loss of R waves and appearance of Q waves in acute myocardial infarction is discussed. A method of praecordial mapping of RS ratio changes and the appearance of Q waves that occur in acute myocardial infarction is described. The serial changes in these electrocardiographic signs in 17 patient...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/11.2.167
更新日期：1977-03-01 00:00:00
abstract：OBJECTIVES:Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This s...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(02)00341-3
更新日期：2002-07-01 00:00:00
abstract：OBJECTIVE:The aim of this work was to compare the effects of supplementation of rat chow diet with potassium (K+) and whey mineral concentrate (Whey), a diet rich in milk minerals, on blood pressure and arterial responses in vitro in spontaneously hypertensive rats (SHR). METHODS:Thirty young SHR and twenty Wistar-Kyo...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(98)00180-1
更新日期：1998-11-01 00:00:00
abstract：OBJECTIVE:Mice with genetic disruption of the guanylyl cyclase-A (GC-A) receptor for atrial natriuretic peptide (ANP), have chronic arterial hypertension and marked cardiac hypertrophy. Intriguingly, despite pronounced remodeling, cardiac contractile functions and cardiomyocyte Ca(2+)-handling are preserved and even en...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2006.10.003
更新日期：2007-03-01 00:00:00
abstract：OBJECTIVES:To characterize the 'anti-ischemic' effects of adenosine metabolism inhibition in ischemic-reperfused myocardium. METHODS:Perfused C57/B16 mouse hearts were subjected to 20 min ischemia 40 min reperfusion in the absence or presence of adenosine deaminase inhibition (50 microM erythro-2-(2-hydroxy-3-nonyl)ad...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(01)00360-1
更新日期：2001-10-01 00:00:00
abstract：Aims:MicroRNAs (miRNAs) have been implicated in the pathogenesis of pulmonary hypertension (PH), a multifactorial and progressive condition associated with an increased afterload of the right ventricle leading to heart failure and death. The main aim of this study was to correlate the levels of miR-424(322) with the se...
journal_title：Cardiovascular research
pub_type： 杂志文章,多中心研究
doi：10.1093/cvr/cvx187
更新日期：2018-01-01 00:00:00
abstract：OBJECTIVE:Exposure to anoxia has been reported to activate ATP-sensitive potassium (K+(ATP)) channels in isolated ventricular myocytes. We aimed to investigate the mechanisms underlying the anoxia-induced activation of K+(ATP) channels. METHODS:Guinea pig ventricular myocytes were isolated using collagenase digestion....
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(97)00092-8
更新日期：1997-08-01 00:00:00
abstract：:The static mechanical properties of major branches of the human arteries (common carotid artery, abdominal aorta, femoral artery, and brachial artery) were studied in 39 subjects, aged 6-81 years, using an ultrasonic phase locked echo tracking system that allows continuous transcutaneous measurement of the diameter of...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/21.9.678
更新日期：1987-09-01 00:00:00
abstract：OBJECTIVE:Inhibitors of poly (ADP-ribose) synthetase (PARS) activity reduce the infarct size caused by regional myocardial ischaemia and reperfusion in the rabbit and rat in vivo. The mechanism of action of these inhibitors is unclear. Here we investigate the effects of the PARS inhibitor 3-aminobenzamide (3-AB) on inf...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(98)00221-1
更新日期：1999-01-01 00:00:00
abstract：AIMS:Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvaa279
更新日期：2020-10-01 00:00:00
abstract：OBJECTIVE:Adenosine inhibits neutrophil adhesion and injury to isolated cardiac myocytes. In the present study, the contribution of selectin and CD18 interactions to neutrophil-myocyte adhesion and their sensitivity to adenosine were assessed. METHODS:Activated human neutrophils and canine myocytes were incubated with...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/0008-6363(96)00052-1
更新日期：1996-08-01 00:00:00
abstract：OBJECTIVE:The primary aim of this study was to investigate whether activation of Na influx via voltage-gated Na channels can elevate sub-sarcolemmal ('fuzzy-space') [Na] and transiently activate Na/K pump current (I(p)). METHODS AND RESULTS:Initially, Na/K pump activity was characterised in whole-cell voltage-clamped ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(02)00645-4
更新日期：2003-03-15 00:00:00
abstract：OBJECTIVE:The aim was to investigate the effect of lowering external potassium on the sensitivity of the normal and hypertrophied rat heart to arrhythmias induced by increases in ventricular wall stress. METHODS:The isolated working heart model was used to compare hypertrophied hearts from the spontaneously hypertensi...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：
更新日期：1995-04-01 00:00:00
abstract：STUDY OBJECTIVE:The aim was to evaluate the thrombolytic efficacy of recombinant double chain tissue plasminogen activator (Duteplase, t-PA) given as a single intravenous bolus versus an infusion in a canine model of coronary arterial occlusion/reperfusion. DESIGN:Coronary arterial thrombi were induced by a copper coi...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/25.3.184
更新日期：1991-03-01 00:00:00
abstract：:The heart responds to ischaemic stimuli with release of negative inotropic mediators such as cytokines, platelet-activating factor, oxygen free radicals, arachidonic acids, nitric oxide, adenosine, and still unidentified "cardiodepressant factors" that modulate myocardial performance via autocrine and paracrine coupli...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(01)00420-5
更新日期：2002-01-01 00:00:00
abstract：OBJECTIVE:The objective of this study was to investigate the relationship between acute decreases in right ventricular volume during Valsalva strain (with resultant changes in autonomic neural tone) and measures of local endocardial repolarization time independent of heart rate and autonomic neural tone. METHODS:Patie...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00261-8
更新日期：2000-01-14 00:00:00
abstract：:Platelet-dependent thrombus formation is a key event in the pathogenesis of acute myocardial infarction (AMI). Platelets mediate both thrombotic occlusion of the entire epicardial coronary artery and also accumulate in the microcirculation resulting in impairment of microcirculation and provoking myocardial ischemia d...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2003.11.036
更新日期：2004-02-15 00:00:00
abstract：AIMS:Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mec...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvaa239
更新日期：2020-08-10 00:00:00
abstract：:The potent anaphylatoxin C3a was measured in the peripheral blood of eleven patients receiving radiocontrast agents whilst undergoing coronary angiography. In seven patients C3a levels were raised during this procedure and in three of these the anaphylatoxin was increased between four and tenfold. In four patients C3a...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/19.2.85
更新日期：1985-02-01 00:00:00
