Abstract:
:Mutations in the human ether-a-go-go-related gene (hERG) result in long QT syndrome type 2 (LQT2). The hERG gene encodes a K(+) channel that contributes to the repolarization of the cardiac action potential. We have previously shown that hERG mRNA transcripts that contain premature termination codon mutations are rapidly degraded by nonsense-mediated mRNA decay (NMD). In this study, we identified a LQT2 nonsense mutation, Q81X, which escapes degradation by the reinitiation of translation and generates N-terminally truncated channels. RNA analysis of hERG minigenes revealed equivalent levels of wild-type and Q81X mRNA while the mRNA expressed from minigenes containing the LQT2 frameshift mutation, P141fs+2X, was significantly reduced by NMD. Western blot analysis revealed that Q81X minigenes expressed truncated channels. Q81X channels exhibited decreased tail current levels and increased deactivation kinetics compared to wild-type channels. These results are consistent with the disruption of the N-terminus, which is known to regulate hERG deactivation. Site-specific mutagenesis studies showed that translation of the Q81X transcript is reinitiated at Met124 following premature termination. Q81X co-assembled with hERG to form heteromeric channels that exhibited increased deactivation rates compared to wild-type channels. Mutant channels also generated less outward current and transferred less charge at late phases of repolarization during ventricular action potential clamp. These results provide new mechanistic insight into the prolongation of the QT interval in LQT2 patients. Our findings indicate that the reinitiation of translation may be an important pathogenic mechanism in patients with nonsense and frameshift LQT2 mutations near the 5' end of the hERG gene.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Stump MR,Gong Q,Packer JD,Zhou Zdoi
10.1016/j.yjmcc.2012.08.021subject
Has Abstractpub_date
2012-11-01 00:00:00pages
725-33issue
5eissn
0022-2828issn
1095-8584pii
S0022-2828(12)00326-4journal_volume
53pub_type
杂志文章abstract:BACKGROUND:Mitochondrial calcium overload is an important factor in defining ischemia/reperfusion injury. Since pre-menopausal women are relatively protected from ischemia and heart disease, we tested the hypothesis that gender differences alter Ca(2+) handling in rat cardiac mitochondria. METHODS:Using cardiac mitoch...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2004.04.023
更新日期:2004-08-01 00:00:00
abstract::The activation of vascular smooth muscle cells (SMCs) in neointimal hyperplasia involves signaling through receptor tyrosine kinases as well as G protein-coupled receptors. Overexpression of G protein-coupled receptor kinase-2 (GRK2) in SMCs can attenuate mitogenic signaling and proliferation in response to not only s...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2002.2092
更新日期:2002-10-01 00:00:00
abstract::The biological function of FAM3A, the first member of family with sequence similarity 3 (FAM3) gene family, remains largely unknown. This study aimed to determine its role in the proliferation and migration of vascular smooth muscle cells (VSMCs). Immunohistochemical staining revealed that FAM3A protein is expressed i...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2014.05.011
更新日期:2014-09-01 00:00:00
abstract::The possible ischemia-selective Class III anti-arrhythmic action (selective action potential widening in ischemia) of the IKATP blocker glibenclamide was assessed in anesthetized rabbits during ischemia induced by complete occlusion of a coronary artery. Coronary artery occlusion caused an initial prolongation in mono...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1998.0664
更新日期:1998-05-01 00:00:00
abstract::Our previous work showed that myosin phosphorylation decreased the ATPase activity of skeletal muscle myofibrils that were lightly fixed with glutaraldehyde. The fixation process prevented sarcomere shortening and destruction of the ordered filament array upon the addition of ATP. We have now extended these results to...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(84)80624-0
更新日期:1984-07-01 00:00:00
abstract::Peroxynitrite and hydroxyl radical are reactive oxidants produced during myocardial reperfusion injury. In various cell types, including macrophages and smooth muscle cells, peroxynitrite and hydrogen peroxide cause DNA single strand breakage, which triggers the activation of the nuclear enzyme poly (ADP-ribose) synth...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1997.0496
更新日期:1997-09-01 00:00:00
abstract::The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) signific...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2004.06.014
更新日期:2004-09-01 00:00:00
abstract::Release of atrial natriuretic peptide (ANP) from atrial muscle cells is thought to occur by exocytosis of secretory granules, as in other secretory systems. However, in the atrial myocyte, exocytosis has previously proved difficult to detect ultrastructurally. In order to study the mechanism of ANP release and related...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/0022-2828(90)90089-k
更新日期:1990-07-01 00:00:00
abstract::Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transf...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2015.05.008
更新日期:2015-08-01 00:00:00
abstract::Although the myocardium is capable of utilizing both glucose and fatty acid substrates, glucose metabolism is inhibited in the presence of fatty acid during normal perfusion conditions. Fatty acid regulation of glucose utilization in intact beating rat hearts was studied with 13C-enriched substrates and 13C and 31P NM...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/0022-2828(89)90787-6
更新日期:1989-05-01 00:00:00
abstract::Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filaments of the sarcomere. Understanding the structural and functional role of cMyBP-C in the heart is clinically relevant since cMyBP-C gene mutations are a widely recognized cause of hypertrophic cardiomyopathy (HCM), which affects 0.2% of the g...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2011.01.014
更新日期:2011-04-01 00:00:00
abstract::Cardiac-specific transgenesis in the mouse is widely used to study the basic biology and chemistry of the heart and to model human cardiovascular disease. A fundamental difference between mouse and human hearts is the background motor protein: mouse hearts contain predominantly the alphaalpha-myosin heavy chain (MyHC)...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2006.08.116
更新日期:2007-01-01 00:00:00
abstract::Effects of ischemia time and treatment interventions upon troponin I (TnI) proteolysis and function of reperfused myocardium were examined in isolated, perfused rabbit hearts. Hearts were randomized to 90 min aerobic perfusion, 15 min low-flow (1 ml/min) ischemia (I) and 60 min reperfusion (R) or 60 min low-flow I and...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.2002.1522
更新日期:2002-04-01 00:00:00
abstract::Previous studies have demonstrated that pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat cardiac mitochondria is increased @two-fold by providing a high-fat diet for 28 days. The present study sought to establish the factor(s) that might underlie the response of cardiac PDHK to the provision of a high-...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1997.0425
更新日期:1997-07-01 00:00:00
abstract::The endoplasmic reticulum (ER) forms discrete junctions with the plasma membrane (PM) that play a critical role in the regulation of Ca2+ signaling during cellular bioenergetics, apoptosis and autophagy. We have previously confirmed that acetylcholine can inhibit ER stress and apoptosis after inflammatory injury. Howe...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2017.04.001
更新日期:2017-06-01 00:00:00
abstract::Cardiac ischemia-reperfusion (I/R) injury always accompanies recanalization treatment for myocardial infarction. Here we found soluble epoxide hydrolase (sEH), which metabolizes cardioprotective epoxyeicosatrienoic acids into less effective diols, was rapidly activated during myocardial reperfusion in both mouse and r...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2017.07.006
更新日期:2017-09-01 00:00:00
abstract::The importance of endogenous and exogenous estrogen levels to the development of cardiovascular disease in women in controversial. The purpose of our study was to examine the effect of estrogen on the development of hypertension, cardiac hypertrophy, ventricular function, and gene expression for atrial natriuretic pep...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1999.0985
更新日期:1999-08-01 00:00:00
abstract::23Na and 31P NMR spectroscopy were used to follow intracellular [Na+] ([Na+]i) and energy metabolism in isolated, perfused rat hearts. During 30 min of Ca(2+)-free perfusion no significant change in [Na+]i could be detected, but during a subsequent 45 min period of ischemia [Na+]i rose significantly as expected, from ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1997.0578
更新日期:1998-01-01 00:00:00
abstract:BACKGROUND:Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitud...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2020.08.008
更新日期:2020-10-01 00:00:00
abstract::Fibroblasts play a pivotal role in cardiac remodeling and the development of heart failure through the deposition of extra-cellular matrix (ECM) proteins and also by affecting cardiomyocyte growth and function. The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system in health and disease and...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2010.12.003
更新日期:2011-10-01 00:00:00
abstract::Sphingomyelin breakdown product ceramide has recently been found to induce an adaptive response and reduce myocardial ischemia/reperfusion injury. Since activation of MAP kinases plays an essential role in myocardial adaptation to ischemic stress and since ceramide is involved in lipid raft formation where MAP kinases...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2006.08.118
更新日期:2007-01-01 00:00:00
abstract::There is increasing momentum toward the development of gene therapy for heart failure (HF) that is defined by impaired calcium (Ca2+) transport and reduced contractility. We have used FRET (fluorescence resonance energy transfer) between fluorescently-tagged SERCA2a (the cardiac Ca2+ pump) and PLB (phospholamban, vent...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2019.11.147
更新日期:2020-01-01 00:00:00
abstract::Activation of both mTOR and its downstream target, S6K1 (p70 S6 kinase) have been implicated to affect cardiac hypertrophy. Our earlier work, in a feline model of 1-48 h pressure overload, demonstrated that mTOR/S6K1 activation occurred primarily through a PKC/c-Raf pathway. To further delineate the role of specific P...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2007.09.015
更新日期:2007-12-01 00:00:00
abstract::Autophagy is an important quality control mechanism present in all cells to maintain their cellular homeostasis. An imbalance in the autophagic process had been reported in numerous diseases including cardiovascular disease and is associated with serious consequences. Thus, knowledge of key regulators of cardiac autop...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2015.11.012
更新日期:2016-06-01 00:00:00
abstract::Diabetes is recognized as an independent risk factor for cardiovascular morbidity and mortality. This is due, in large part, to premature atherosclerosis, enhanced thrombogenicity and activation of systemic inflammatory programs with resultant vascular dysfunction. More enigmatic mechanisms underpinning diabetes-assoc...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2009.02.001
更新日期:2009-06-01 00:00:00
abstract::The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of T...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2016.04.006
更新日期:2016-08-01 00:00:00
abstract::Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global ...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2014.01.015
更新日期:2014-04-01 00:00:00
abstract::The aim of this study was to examine whether short- and long-term gene transfer of Ca(2+) handling proteins restore left ventricular (LV) mechanoenergetics in aortic banding-induced failing hearts. Aortic-banded rats received recombinant adenoviruses carrying sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) (Banding+SER...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2007.01.003
更新日期:2007-04-01 00:00:00
abstract::In the past decade, genetic modification has been extensively employed to define (patho)physiological roles of chaperones and the cytoskeleton in the heart, promoting dramatic advances in this field. Both loss-of-function and gain-of-function approaches have been used productively. alphaB-Crystallin (CryAB) is the mos...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
doi:10.1016/j.yjmcc.2004.07.004
更新日期:2004-12-01 00:00:00
abstract::Although protection against necrosis has been observed in both hibernating (HIB) and ischemic preconditioned hearts in the second window of protection (SWOP), a comparison of the mitochondrial proteome between the two entities has not been previously performed. Anesthetized swine underwent instrumentation with a fixed...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2013.03.018
更新日期:2013-07-01 00:00:00