Abstract:
AIMS:Altered Ca(2+) handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP1 on different subcellular targets such as ryanodine receptor type 2 (RyR2), especially in AF. METHODS AND RESULTS:We tested the hypothesis that impaired local regulation of PP1 causes RyR2 hyperphosphorylation thereby promoting AF susceptibility. To specifically disrupt PP1's local regulation of RyR2, we used the spinophilin knockout (Sp(-/-)) mice (Mus musculus) since PP1 is targeted to RyR2 via spinophilin. Without spinophilin, the interaction between PP1 and RyR2 was reduced by 64%, while RyR2 phosphorylation was increased by 43% at serine (S)2814 but unchanged at S2808. Lipid bilayer experiments revealed that single RyR2 channels isolated from Sp(-/-) hearts had an increased open probability. Likewise, Ca(2+) spark frequency normalized to sarcoplasmic reticulum Ca(2+) content was also enhanced in Sp(-/-) atrial myocytes, but normalized by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-93 and AIP and also by genetic inhibition of RyR2 S2814 phosphorylation. Finally, Sp(-/-) mice exhibited increased atrial ectopy and susceptibility to pacing-induced AF, both of which were also prevented by the RyR2 S2814A mutation. CONCLUSION:PP1 regulates RyR2 locally by counteracting CaMKII phosphorylation of RyR2. Decreased local PP1 regulation of RyR2 contributes to RyR2 hyperactivity and promotes AF susceptibility. This represents a novel mechanism for subcellular modulation of calcium channels and may represent a potential drug target of AF.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Chiang DY,Li N,Wang Q,Alsina KM,Quick AP,Reynolds JO,Wang G,Skapura D,Voigt N,Dobrev D,Wehrens XHdoi
10.1093/cvr/cvu123subject
Has Abstractpub_date
2014-07-01 00:00:00pages
178-87issue
1eissn
0008-6363issn
1755-3245pii
cvu123journal_volume
103pub_type
杂志文章abstract:AIMS:This study examines the effect of endogenous male sex hormones on thromboxane A2 (TXA2), prostaglandin (PG) I2, PGF(2 alpha), and PGE I2 release, as well as their role in acetylcholine (ACh)-mediated relaxation in the aorta. METHODS AND RESULTS:Aortic segments from orchidectomized and control male Sprague-Dawley ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvm059
更新日期:2008-02-01 00:00:00
abstract:OBJECTIVE:We propose that ischemic preconditioning (IPC) and mitochondrial K(ATP) channel activation protect the myocardium by inhibiting mitochondrial permeability transition pore (MPTP) opening at reperfusion. METHODS:Isolated rat hearts were subjected to 35 min ischemia/120 min reperfusion and assigned to the follo...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00455-8
更新日期:2002-08-15 00:00:00
abstract:OBJECTIVES:Myocardial ischemia results in an early phase of arrhythmias that primarily involves reentrant mechanisms. However, the trigger that initiates reentry remains unknown. We studied the initiation of reentry attending the development of electrical heterogeneity during simulated ischemia in isolated canine right...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::Angiotensin II (AII) plays a critical role in cardiac remodeling. This peptide promotes cardiac myocyte hypertrophy and cardiac fibroblast interstitial fibrotic changes associated with left ventricular hypertrophy, post myocardial infarction remodeling and congestive heart failure. AII mediates cardiac myocyte hypertr...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(00)00044-4
更新日期:2000-05-01 00:00:00
abstract:OBJECTIVE:The aim was to correlate the relative abilities of amiodarone, lignocaine, and penticainide in suppressing ventricular tachyarrhythmias in response to coronary artery occlusion with their relative abilities to prolong ventricular functional refractory periods and to reduce intraventricular conduction velociti...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.11.1116
更新日期:1992-11-01 00:00:00
abstract:AIMS:Vascular endothelial growth factors (VEGFs) and their receptors (VEGF-Rs) are among the most powerful factors regulating vascular growth. However, it has remained unknown whether stimulation of VEGF-R1, VEGF-R2 or both of the receptors produces the best angiogenic responses in myocardium. The aim of this study was...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvp382
更新日期:2010-04-01 00:00:00
abstract:AIMS:Imbalance between pro- and antioxidant species (e.g. during aging) plays a crucial role for vascular function and is associated with oxidative gene regulation and modification. Vascular aging is associated with progressive deterioration of vascular homeostasis leading to reduced relaxation, hypertrophy, and a high...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn182
更新日期:2008-11-01 00:00:00
abstract:OBJECTIVE:The aim was to compare differences in peak twitch force occurring despite similar degrees of right ventricular hypertrophy in ferrets with pulmonary artery banding at either weanling or juvenile age. METHODS:After inducing pressure overload hypertrophy by banding the pulmonary artery of weanling and juvenile...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract:AIMS:AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvv166
更新日期:2015-07-15 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:AIMS:To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. METHODS AND RESULTS:National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 pati...
journal_title:Cardiovascular research
pub_type: 杂志文章,多中心研究
doi:10.1093/cvr/cvz197
更新日期:2020-01-01 00:00:00
abstract::Cardiac hypertrophy was induced in rabbits at atmospheric pressure by exposing them to hypoxia equivalent to an altitude of 6000 m for 280 to 350 h. Intracellular action potentials were recorded from Purkinje cells, and from atrial and papillary muscles, contractions of which were also measured. Hearts from normoxic l...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/18.10.597
更新日期:1984-10-01 00:00:00
abstract::Electrophysiologic remodeling is a process whereby heart disease alters the electrophysiologic properties of cardiac tissue. These alterations, in turn, can cause or exacerbate disease-related arrhythmias. Ion channels are the fundamental molecular units underlying cardiac electrophysiology, and it therefore follows t...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(99)00063-2
更新日期:1999-05-01 00:00:00
abstract:OBJECTIVE:Increased cardiac collagen is seen in uninephrectomised rats made hypertensive by aldosterone infusion and high salt, with the possibility of a direct effect of aldosterone at the level of the cardiac fibroblast. The aim of this study was to examine the effects of aldosterone, glucocorticoids, and angiotensin...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.12.1863
更新日期:1994-12-01 00:00:00
abstract::The kinetics of onset of rate-dependent depression of maximum rate of depolarisation (Vmax) of guinea-pig ventricular action potentials were studied for nine Class I anti-arrhythmic drugs using standard microelectrode techniques. The drugs were found to fall into three well-demarcated subgroups with "fast" (lignocaine...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/17.6.344
更新日期:1983-06-01 00:00:00
abstract::Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissectio...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvy006
更新日期:2018-03-15 00:00:00
abstract:OBJECTIVE:Previous studies have shown that chronic cardiac denervation impairs myocardial glucose oxidation. To investigate this further we tested whether the tissue content of glucose transporters, activity of glycolytic enzymes or metabolic capacity of pyruvate dehydrogenase were altered. Moreover, we investigated wh...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00220-4
更新日期:1998-01-01 00:00:00
abstract::The structural basis for the development of congestive heart failure (CHF) is a maladaptive myocardial remodeling process which occurs secondarily to post-myocardial infarction (MI), hypertensive hypertrophy, or cardiomyopathy. Both cellular and extracellular factors are involved in the remodeling process and it is th...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2005.10.004
更新日期:2006-02-15 00:00:00
abstract:OBJECTIVE:Lower limb perfusion following arterial occlusion depends on the recruitment of collateral vessels. Blood flow through these collateral vessels may be jeopardized by hypersensitivity to vasoconstriction by serotonin (5-HT), as has been reported during hyperlipidemia and diabetes. Therefore the aim of this stu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00538-2
更新日期:2002-11-01 00:00:00
abstract::The rate of QT adaptation to abrupt changes in pacing rate was studied in seven patients with newly diagnosed complete heart block with a ventricular escape rate of less than 40 beats.min-1. Their median age was 70 (range 36-84) years, and none was taking any cardioactive medication known to affect the QT interval. Fr...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/22.1.67
更新日期:1988-01-01 00:00:00
abstract:OBJECTIVES:We measured the uptake of technetium-99m tetrofosmin (99m Tc) and thallium-201 (201 TI) in areas of healed transmural myocardial infarction and in the regions of acute peri-infarction ischemia. METHODS:Anesthetised pigs with a 1-month old transmural infarction elicited by permanent ligature of the left ante...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00316-7
更新日期:1998-04-01 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::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::Reperfusion of the heart after a period of ischaemia leads to the opening of a nonspecific pore in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore (MPTP). This transition causes mitochondria to become uncoupled and capable of hydrolysing rather than synthesising ATP. Unrestrai...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/S0008-6363(03)00533-9
更新日期:2004-02-15 00:00:00
abstract:AIMS:Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R mice) were shown to have elevated cerebrovascular tone ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvz306
更新日期:2020-10-01 00:00:00
abstract::Tension and action potentials have been measured simultaneously from isolated cat papillary muscles. Two groups of experiments are described. In the first group, the external conditions under which the muscle contracted were changed. Specifically, stimulation rate, extra-cellular [Ca++], extracellular [Na++] were alte...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/11.3.210
更新日期:1977-05-01 00:00:00
abstract:OBJECTIVE:To study the effect of cardiac contraction on left coronary artery pressure-flow relations at different vascular volumes and to compare these relations in the beating heart with those in the heart arrested in systole and diastole. METHODS:Maximally vasodilated, Tyrode perfused, rabbit hearts (n = 6) with an ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00119-9
更新日期:1998-10-01 00:00:00
abstract:OBJECTIVE:Cholinergic vasodilation has been thought to play little if any role in the regulation of blood pressure in humans. Autonomic denervation potentiates the vasoconstriction evoked by nitric oxide synthase inhibition in humans, but the mechanism is unclear. We hypothesized that this may be related to loss of neu...
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
abstract::The signal transducer and activator of transcription 3 (STAT3) is fundamental for physiological homeostasis and stress-induced remodelling of the heart as deregulated STAT3 circuits are sufficient to induce dilated and peripartum cardiomyopathy and adverse remodelling after myocardial infarction. STAT3 activity depend...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvu034
更新日期:2014-05-01 00:00:00
abstract:UNLABELLED:Recent investigations have established the feasibility of using exogenously delivered angiogenic growth factors to increase collateral artery development in animal models of myocardial and hindlimb ischemia. OBJECTIVE:Our aim was to evaluate the ability of a stabilized form of acidic fibroblast growth facto...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00522-4
更新日期:2003-10-01 00:00:00