Abstract：
AIMS:Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit skeletal muscle or pig cardiac muscle, respectively. In heart failure, RyR2 dysfunction is implicated in fatal arrhythmia and RyR1 dysfunction is associated with muscle fatigue. A controversial underlying mechanism of RyR1/2 dysfunction is proposed to be hyperphosphorylation of RyR1/2 by PKA, causing loss of FKBP12/12.6 binding that is reversible by the experimental inhibitory drug K201 (JTV519). Phosphorylation is also a trigger for fatal arrhythmia in catecholaminergic polymorphic ventricular tachycardia associated with point mutations in RyR2. METHODS AND RESULTS:Equilibrium binding kinetics of RyR1/2 to FKBP12/12.6 were measured using surface plasmon resonance (Biacore). Free Ca(2+) concentration was used to modulate the open/closed conformation of RyR1/2 channels measured using [(3)H]ryanodine binding assays. The affinity constant-K(A), for RyR1/2 binding to FKBP12/12.6, was significantly greater for the closed compared with the open conformation. The effect of phosphorylation or K201 was to reduce the K(A) of the closed conformation by increasing the rate of dissociation k(d). K201 reduced [(3)H]ryanodine binding to RyR1/2 at all free Ca(2+) concentrations including PKA phosphorylated preparations. CONCLUSION:The results are explained through a model proposing that phosphorylation and K201 acted similarly to change the conformation of RyR1/2 and regulate FKBP12/12.6 binding. K201 stabilized the conformation, whereas phosphorylation facilitated a subsequent molecular event that might increase the rate of an open/closed conformational transition.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Blayney LM,Jones JL,Griffiths J,Lai FAdoi
10.1093/cvr/cvp273subject
Has Abstractpub_date
2010-01-01 00:00:00pages
68-78issue
1eissn
0008-6363issn
1755-3245pii
cvp273journal_volume
85pub_type
杂志文章abstract：OBJECTIVE:Current guidelines are controversial regarding exercise intensity in cardiovascular prevention and rehabilitation. Although high-intensity training induces larger increases in fitness and maximal oxygen uptake (VO(2max)), moderate intensity is often recommended as equally effective. Controlled preclinical stu...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2005.03.010
更新日期：2005-07-01 00:00:00
abstract：:Currently, a high carbohydrate/low fat diet is recommended for patients with hypertension; however, the potentially important role that the composition of dietary fat and carbohydrate plays in hypertension and the development of pathological left ventricular hypertrophy (LVH) has not been well characterized. Recent st...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2006.11.007
更新日期：2007-01-15 00:00:00
abstract：:When the vagus nerves are stimulated with one burst of pulses per minute, but each burst is placed at a different time in the cardiac cycle, a "vagal effect curve" can be derived which displays the changes in cardiac cycle length (CCL) as a function of the elapsed time from the stimulus. This curve consists of a prima...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/18.2.75
更新日期：1984-02-01 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：:The association of nitric oxide (NO) with cardiovascular disease has long been recognized and the extensive research on this topic has revealed both pro- and anti-atherosclerotic effects. While these contradictory findings were initially perplexing recent studies offer molecular mechanisms for the integration of these...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/s0008-6363(00)00086-9
更新日期：2000-08-18 00:00:00
abstract：:Numerous epidemiological studies documented an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the extent of atherosclerotic disease. However, clinical interventions targeting HDL cholesterol failed to show clinical benefits with respect to cardiovascular risk reduction, sugge...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvu136
更新日期：2014-08-01 00:00:00
abstract：AIMS:Hypertension is accompanied by structural remodelling of vascular extracellular matrix (ECM). Tissue inhibitor of metalloproteinases (TIMPs) inhibits matrix metalloproteinases (MMPs) that degrade the matrix structural proteins. In response to a hypertensive stimulus, the balance between MMPs and TIMPs is altered. ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvt067
更新日期：2013-06-01 00:00:00
abstract：OBJECTIVE:The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS:Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(98)00239-9
更新日期：1999-03-01 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：AIMS:Following a large myocardial infarction (MI), remaining viable muscle often undergoes pathological remodelling and progresses towards chronic heart failure. Mitochondria may also be affected by this process and, due to their functional importance, likely contribute to the progression of the disease. Aerobic interv...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvt080
更新日期：2013-07-01 00:00:00
abstract：OBJECTIVE:The endothelium is a newly recognised target tissue of parathyroid hormone (PTH). It is not clear whether hyperparathyroidism affects endothelial function and whether parathyroidectomy (Ptx) has an influence on arterial vessel wall properties. We studied brachial flow-mediated vasodilation (FMD) and brachial ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(00)00130-9
更新日期：2000-09-01 00:00:00
abstract：OBJECTIVE:Apolipoprotein E-deficient mice (apoE(-/-)) on a regular diet become hypercholesterolemic and develop atherosclerosis, but endothelium-dependent relaxation remains undisturbed for up to 6 months. We investigated whether vasomotor dysfunction develops in aged apoE(-/-), whether the defect was systemic (hyperch...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(03)00353-5
更新日期：2003-07-01 00:00:00
abstract：OBJECTIVE:The acute administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 inductio...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00058-9
更新日期：1999-07-01 00:00:00
abstract：AIMS:Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other i...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvw083
更新日期：2016-08-01 00:00:00
abstract：OBJECTIVE:Left ventricular assist devices (LVAD) have been used to 'bridge' patients with end-stage heart failure to transplantation. Although several reports have suggested that the native ventricular function recovers after long-term LVAD support, a process called 'reverse remodeling', the underlying biological mecha...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(01)00433-3
更新日期：2002-01-01 00:00:00
abstract：AIMS:Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1....
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvu250
更新日期：2015-02-01 00:00:00
abstract：OBJECTIVE:Atrial (ANP) and B-type natriuretics peptides (BNP) via their guanylyl cyclase-A (GC-A) receptor not only regulate arterial blood pressure and volume but also exert local antihypertrophic, antifibrotic and lusitropic effects in the heart. To elucidate whether cardiac hypertrophy/insufficiency and reversal is ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2004.07.004
更新日期：2004-11-01 00:00:00
abstract：:Atherosclerosis is considered to be a form of chronic inflammation governed by a complex network of inter- and intra-cellular signaling pathways. The pleiotropic cytokine interferon-gamma (IFN-gamma) is a key pro-inflammatory mediator that is expressed at high levels in atherosclerotic lesions. IFN-gamma regulates the...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2005.04.019
更新日期：2005-07-01 00:00:00
abstract：:The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wa...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1093/cvr/cvx148
更新日期：2017-10-01 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：:Elevated sympathetic activity changes renal function and accelerates the development of hypertension. Principles of sympatho-renal interactions in chronic hypertension are reviewed. Alterations in the ontogeny of the sympathetic nervous system and the kidney, inherited abnormalities in sensory receptor function and ex...
journal_title：Cardiovascular research
pub_type： 杂志文章,评审
doi：10.1016/j.cardiores.2003.11.024
更新日期：2004-02-01 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: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 abno...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvv152
更新日期：2015-07-01 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:n-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochr...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvq411
更新日期：2011-05-01 00:00:00
abstract：:We studied the effects of intracoronary vasopressin on the relationship between pressure and flow in the coronary circulation of anaesthetised swine. In addition to measurements at control levels, diastolic pressure-flow relationships were constructed from steady-state points below a coronary pressure of 50 mmHg, wher...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/19.7.433
更新日期：1985-07-01 00:00:00
abstract：OBJECTIVE:Mechanoelectric Feedback, a mechanical intervention inducing an electrical change, is gaining credence as a cause of cardiac arrhythmia in the clinical situation. However, the precise mechanism is unknown. To elucidate this we investigated mechanical and chemical modulation of stretch-induced premature ventri...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(97)00314-3
更新日期：1998-04-01 00:00:00
abstract：OBJECTIVE:Persistent atrial fibrillation (AF) results in an impairment of atrial function. In order to elucidate the mechanism behind this phenomenon, we investigated the gene expression of proteins influencing calcium handling. METHODS:Right atrial appendages were obtained from eight patients with paroxysmal AF, ten ...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/s0008-6363(99)00045-0
更新日期：1999-05-01 00:00:00
abstract：AIMS:Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on proge...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1093/cvr/cvn244
更新日期：2009-01-01 00:00:00
abstract：OBJECTIVE:The mechanosensitive nonselective cation channel (NSC(MS)) and endothelin-1 (ET-1) play critical roles in the regulation of vascular tone. This study was undertaken to investigate the effect of ET-1 on NSC(MS) and on the myogenic response of arteries. METHODS:Cell-attached patch-clamp techniques were applied...
journal_title：Cardiovascular research
pub_type： 杂志文章
doi：10.1016/j.cardiores.2007.06.021
更新日期：2007-11-01 00:00:00
