Abstract:
:Heart failure is associated with death of cardiomyocytes leading to loss of contractility. Previous studies using membrane-targeted Akt (myristolated-Akt), an enzyme involved in antiapoptotic signaling, showed inhibition of cell death and prevention of pathogenesis induced by cardiomyopathic stimuli. However, recent studies by our group have found accumulation of activated Akt in the nucleus, suggesting that biologically relevant target(s) of Akt activity may be located there. To test this hypothesis, a targeted Akt construct was created to determine the antiapoptotic action of nuclear Akt accumulation. Nuclear localization of the adenovirally encoded Akt construct was confirmed by confocal microscopy. Cardiomyocytes expressing nuclear-targeted Akt showed no evidence of morphological remodeling such as altered myofibril density or hypertrophy. Nuclear-targeted Akt significantly elevated levels of phospho-Akt and kinase activity and inhibited apoptosis as effectively as myristolated-Akt in hypoxia-induced cell death. Transgenic overexpression of nuclear-targeted Akt did not result in hypertrophic remodeling, altered cardiomyocyte DNA content or nucleation, or enhanced phosphorylation of typical cytoplasmic Akt substrates, yet transgenic hearts were protected from ischemia-reperfusion injury. Gene array analyses demonstrated changes in the transcriptional profile of Akt/nuc hearts compared with nontransgenic controls distinct from prior characterizations of Akt expression in transgenic hearts. Collectively, these experiments show that targeting of Akt to the nucleus mediates inhibition of apoptosis without hypertrophic remodeling, opening new possibilities for therapeutic applications of nuclear-targeted Akt to inhibit cell death associated with heart disease.
journal_name
Circ Resjournal_title
Circulation researchauthors
Shiraishi I,Melendez J,Ahn Y,Skavdahl M,Murphy E,Welch S,Schaefer E,Walsh K,Rosenzweig A,Torella D,Nurzynska D,Kajstura J,Leri A,Anversa P,Sussman MAdoi
10.1161/01.RES.0000124394.01180.BEsubject
Has Abstractpub_date
2004-04-16 00:00:00pages
884-91issue
7eissn
0009-7330issn
1524-4571pii
01.RES.0000124394.01180.BEjournal_volume
94pub_type
杂志文章abstract::To determine the effects of aging on the human myocardium, 67 hearts were obtained from individuals who died from causes other than cardiovascular disease. The age interval examined was 17-90 years. Regression analysis demonstrated that the aging process was characterized by a loss of 38 million and 14 million myocyte...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.6.1560
更新日期:1991-06-01 00:00:00
abstract::A new protocol has been developed for selective removal of the endothelium from the arteries of the perfused rat hind-limb preparation. The hind limb was perfused with oxygenated Krebs-Ringer bicarbonate solution with a combination of high flow and timed air bubbles (2 minutes at high flow followed by 5 minutes of air...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.6.1190
更新日期:1989-06-01 00:00:00
abstract::In recent year, increasing evidence suggests that noncoding RNAs play important roles in the regulation of tissue homeostasis and pathophysiological conditions. Besides small noncoding RNAs (eg, microRNAs), >200-nucleotide long transcripts, namely long noncoding RNAs (lncRNAs), can interfere with gene expressions and ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.116.302521
更新日期:2015-02-13 00:00:00
abstract::Although morphological studies suggest that coronary vascular injury is a result of prolonged ischemia and subsequent reperfusion, whether functional coronary microvascular injury develops during brief in vivo ischemia is unclear. In other organs, permeability is a sensitive indicator of functional vascular injury. Th...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.4.986
更新日期:1990-04-01 00:00:00
abstract::The mechanism of adenosine-induced inhibition of Ca2+ currents was studied by recording single-channel Ca2+ currents from cell-attached patches on isolated guinea pig ventricular cells with pipettes containing 50 or 100 mM Ba2+. Numerous 100-msec depolarization steps were applied repetitively at 2 Hz from the resting ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.67.5.1134
更新日期:1990-11-01 00:00:00
abstract:RATIONALE:Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. OBJECTIVE:We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival. METHODS AND RESULTS:We use...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.303632
更新日期:2014-07-18 00:00:00
abstract::A method was developed for recording isometric tension from isolated small arteries (mean internal diameter, 169 microns) and veins (mean internal diameter, 273 microns) of the term fetal lung and was then applied to the study of the mechanisms controlling perinatal pulmonary hemodynamics. The specific purpose was to ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.2.320
更新日期:1992-08-01 00:00:00
abstract::To clarify the physiological role of calcium-activated neutral protease (CANP) in human platelets, we loaded the platelets with a Ca2+ -sensitive fluorescent dye, fura-2, and measured the degree of aggregation, cytosolic calcium ion concentration [( Ca2+]i), and proteolysis by sodium dodecyl sulfate-polyacrylamide gel...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.2.407
更新日期:1989-02-01 00:00:00
abstract::This study aimed to characterize the interaction between nitric oxide (NO)- and cAMP-related pathways in the control of renal blood flow. Using the isolated perfused rat kidney model, we determined the effects of inhibition of NO formation by Nomega-nitro-L-arginine methyl ester (L-NAME; 1 mmol/L) and of NO administra...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.84.2.186
更新日期:1999-02-05 00:00:00
abstract::We have observed that acute medial cell loss is an initial event in the response to vascular injury induced by balloon-catheter distention of the rabbit carotid artery. Numerous apoptotic medial cells were observed as early as 30 minutes after balloon inflation, and a 70% loss of cellularity was evident by 90 minutes....
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.84.1.113
更新日期:1999-01-08 00:00:00
abstract:RATIONALE:We previously reported that vascular endothelial growth factor (VEGF)-induced binding of VEGF receptor 2 (VEGFR2) to epsins 1 and 2 triggers VEGFR2 degradation and attenuates VEGF signaling. The epsin ubiquitin interacting motif (UIM) was shown to be required for the interaction with VEGFR2. However, the mole...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.307679
更新日期:2016-03-18 00:00:00
abstract:RATIONALE:Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.305347
更新日期:2015-04-10 00:00:00
abstract::Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000235869.50747.e1
更新日期:2006-08-04 00:00:00
abstract::The aim of this study is to quantify the porcine coronary arterial branching pattern and to use this quantification for the interpretation of flow heterogeneity. Two casts of the coronary arterial tree were made at diastolic arrest and maximal dilation. The relation between length and diameter of arterial segments was...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.5.1200
更新日期:1992-11-01 00:00:00
abstract::High affinity binding sites of angiotensin II (A II) have been characterized in rabbit renomedullary interstitial cells in tissue culture. Binding was rapid, specific, and saturable. Scatchard analysis of steady state saturation binding data at 22 degrees C indicated a single binding site with an equilibrium dissociat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.46.6.802
更新日期:1980-06-01 00:00:00
abstract::We have cloned from cultured vascular smooth muscle cells a protein tyrosine phosphatase, rat density-enhanced phosphatase-1 (rDEP-1), which is a probable rat homologue of DEP-1/HPTP eta. rDEP-1 is encoded by an 8.7-kb transcript and is expressed as a 180- to 220-kD protein. The rDEP-1 gene is located on human chromos...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.79.3.570
更新日期:1996-09-01 00:00:00
abstract::Nitric oxide (NO) exerts important vasodilatory, antiplatelet, antioxidant, antiadhesive, and antiproliferative effects. Although endothelium derived NO has been shown to be of prime importance in cardio- and vasculoprotection, until recently little was known about the role of platelet-derived NO. New evidence suggest...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.107.158410
更新日期:2007-09-28 00:00:00
abstract:RATIONALE:G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising th...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.112.300754
更新日期:2013-04-12 00:00:00
abstract::We tested the hypothesis that a parenchymally derived mediator is required for arterioles to exhibit oxygen sensitivity. To that end, the parenchyma was dissected and removed from around hamster cheek pouch arterioles, and the oxygen sensitivity of these "aparenchymal arteriolar segments" was studied, either in vitro,...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.53.4.515
更新日期:1983-10-01 00:00:00
abstract::The spatial and dynamic properties of ventricular fibrillation (VF) may be random or related to cellular electrical properties of the normal heart. Local activation intervals (AIs) in VF may depend on the local refractory period (RP), and sustained VF may require a steep action potential (AP) restitution curve. In gui...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.88.5.e49
更新日期:2001-03-16 00:00:00
abstract::Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000029970.97247.57
更新日期:2002-08-09 00:00:00
abstract::During an investigation of the effect of ryanodine on contractions in cardiac muscle, it was found that long rest periods removed all or most of the drug's effect. Therefore, we studied the kinetics of block development and recovery from block produced by low concentrations of ryanodine (1-100 pM) on the postrest cont...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.60.4.560
更新日期:1987-04-01 00:00:00
abstract::When exposed to an increasing transmural pressure, middle cerebral arteries of the cat exhibit reduction of internal diameter which is mediated by vascular muscle cell depolarization. This laboratory has recently demonstrated that this "pressure-induced" activation is dependent upon the presence of an intact endotheli...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.1.193
更新日期:1989-07-01 00:00:00
abstract::Changes in cardiac filling pressure (central venous pressure) were measured following carotid occlusion and infusions of catecholamines in awake dogs while cardiac output was held constant. After carotid occlusion in dogs with vagi blocked, central venous pressure increased about 0.8 mm Hg (an estimated decrease in va...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.55.4.440
更新日期:1984-10-01 00:00:00
abstract:RATIONALE:The cardiac inwardly rectifying K(+) current (I(K1)) plays a critical role in modulating excitability by setting the resting membrane potential and shaping phase 3 of the cardiac action potential. OBJECTIVE:This study aims to analyze the effects of nitric oxide (NO) on human atrial I(K1) and on Kir2.1 channe...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.197558
更新日期:2009-08-14 00:00:00
abstract::Electrical propagation in the normal heart occurs via intercellular transfer of current at gap junctions. Alterations in intercellular coupling in the diseased heart are critical in the pathogenesis of reentrant ventricular arrhythmias. Until recently only a single gap junction protein was known to couple cardiac myoc...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.2.438
更新日期:1992-02-01 00:00:00
abstract:RATIONALE:The impact of severe cardiovascular disease and critical limb ischemia (CLI) on the bone marrow (BM) is largely unknown. OBJECTIVE:To investigate microvascular and neuropathic changes in BM of patients with CLI. METHODS AND RESULTS:BM biopsies were obtained from patients with CLI (n=33) included in the Reju...
journal_title:Circulation research
pub_type: 临床试验,杂志文章
doi:10.1161/CIRCRESAHA.114.302791
更新日期:2014-01-17 00:00:00
abstract::We used plethysmograph techniques to measure or calculate the tissue and capillary forces and flows (capillary pressure, tissue and plasma oncotic pressure, transcapillary pressure drop, lymph flow, and interstitial pressure) in a dog hindpaw preparation in situ at three different venous pressures (PV). Since lymph wa...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.39.2.245
更新日期:1976-08-01 00:00:00
abstract::Recent advances in cardiac physiology identify the integrin-linked kinase (ILK) as an essential molecule regulating cardiac growth, contractility, and repair. A key transducer of biochemical signals initiated at the plasma membrane by cell-matrix interactions, ILK now emerges as a crucial player in mechanotransduction...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.RES.0000265233.40455.62
更新日期:2007-05-25 00:00:00
abstract::RNA splicing represents a post-transcriptional mechanism to generate multiple functional RNAs or proteins from a single transcript. The evolution of RNA splicing is a prime example of the Darwinian function follows form concept. A mutation that leads to a new mRNA (form) that encodes for a new functional protein (func...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.115.307872
更新日期:2016-02-05 00:00:00