Abstract:
:The mechanism(s) by which mutations in sarcomeric proteins cause hypertrophic cardiomyopathy (HCM) remains unknown. A leading hypothesis proposes that mutant sarcomeric proteins impair cardiac myocyte contractility, providing an impetus for compensatory hypertrophy. To test this hypothesis, we determined the impact of expression of a mutant (Arg92Gln) human cardiac troponin T (cTnT), known to cause HCM in humans, on adult cardiac myocyte contractility. A full-length human cTnT cDNA was cloned, and the Arg92Gln mutation was induced. Recombinant adenoviruses Ad5/CMV/cTnT-N and Ad5/CMV/cTnT-Arg92Gln were generated through homologous recombination. Adult feline cardiac myocytes were infected with recombinant adenoviruses or a control viral vector (Ad5 delta E1) at a multiplicity of infection of 100. Expression levels of the full-length normal and mutant cTnT proteins were equal on Western blots. Expression of the exogenous cTnT proteins in cardiac myocytes was also shown by immunocytochemistry and immunofluorescence, and their incorporation into myofibrils was confirmed by Western blotting on myofibrillar extracts. Electron microscopy showed intact sarcomere structure in rod-shaped cardiac myocytes in all groups. Cell fractional shortening and the peak velocity of shortening were not significantly different among the groups 24 hours after transduction. However, 48 hours after transduction, both fractional shortening and the peak velocity of shortening were significantly reduced (24% [P < .001] and 26% [P < .001], respectively) in cardiac myocytes in the Ad5/CMV/cTnT-Arg92Gln compared with the Ad5/CMV/cTnT-N groups. The magnitude of the reductions was greater at 72 hours after transduction (45% and 39%, respectively; P < .001). Our results indicated that expression of the mutant (Arg92Gln) cTnT, known to cause HCM in humans, impaired intact adult cardiac myocyte contractility. Our data also show that both normal and mutant cTnT were incorporated into myofibrils. These results provide a potential mechanism by which mutations in sarcomeric proteins cause HCM.
journal_name
Circ Resjournal_title
Circulation researchauthors
Marian AJ,Zhao G,Seta Y,Roberts R,Yu QTdoi
10.1161/01.res.81.1.76subject
Has Abstractpub_date
1997-07-01 00:00:00pages
76-85issue
1eissn
0009-7330issn
1524-4571journal_volume
81pub_type
杂志文章abstract:RATIONALE:Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair. OBJECTIV...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.301152
更新日期:2013-07-05 00:00:00
abstract::Choline acetyltransferase is the enzyme that catalyzes the biosynthesis of acetylcholine, the neurotransmitter of the pre- and postganglionic parasympathetic system. To assess the extent of parasympathetic innervation, enzyme activity was measured in specialized and contractile regions throughout the guinea pig heart....
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.42.5.657
更新日期:1978-05-01 00:00:00
abstract::During cardiac development, the epicardium is the source of multipotent mesenchymal cells, which give rise to endothelial and smooth muscle cells in coronary vessels and also, possibly, to cardiomyocytes. The aim of the present study was to determine whether stem cells are retained in the adult human and murine epicar...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.150755
更新日期:2007-12-07 00:00:00
abstract:RATIONALE:Macrophages are essential regulators of atherosclerosis. They secrete cytokines, process lipoproteins and cholesterol, and take up apoptotic cells. Multiple subsets of plaque macrophages exist and their differential roles are emerging. OBJECTIVE:Here, we explore macrophage heterogeneity in atherosclerosis pl...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.119.315175
更新日期:2019-12-06 00:00:00
abstract::Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.116.309140
更新日期:2017-03-17 00:00:00
abstract::Isolated cardiac conduction disease is an autosomal dominant defect that includes various combinations of bundle branch or fascicular blocks. These defects can cause sudden death due to a complete heart block. We used a genome-wide screening approach with polymorphic (CA)n repeat markers to determine the chromosomal p...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.77.4.735
更新日期:1995-10-01 00:00:00
abstract::Heart failure (HF) has been singled out as an epidemic and is a staggering clinical and public health problem, associated with significant mortality, morbidity, and healthcare expenditures, particularly among those aged ≥ 65 years. The case mix of HF is changing over time with a growing proportion of cases presenting ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.113.300268
更新日期:2013-08-30 00:00:00
abstract::Peroxisome proliferator-activated receptor (PPAR) gamma is activated by thiazolidinediones (TZDs), widely used as insulin-sensitizing agents for the treatment of type 2 diabetes. TZDs have been shown to induce apoptosis in a variety of mammalian cells. In vascular smooth muscle cells (VSMCs), proliferation and apoptos...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000088344.15288.E6
更新日期:2003-08-22 00:00:00
abstract::Deepak Srivastava’s group at the Gladstone Institute of Cardiovascular Disease, University of California San Francisco, reported in the August 6 issue of the journal Cell that to make heart muscle cells, all you need are three factors and some fibroblasts. But is it really that easy? ...
journal_title:Circulation research
pub_type: 新闻
doi:10.1161/RES.0b013e3181ffeac0
更新日期:2010-10-29 00:00:00
abstract:BACKGROUND:Myocyte contractile dysfunction occurs in pathological remodeling in association with abnormalities in calcium regulation. Mice with cardiac myocyte-specific overexpression of Galphaq develop progressive left ventricular failure associated with myocyte contractile dysfunction and calcium dysregulation. OBJE...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.217570
更新日期:2010-07-23 00:00:00
abstract:RATIONALE:Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). OBJECTIVE:To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. MET...
journal_title:Circulation research
pub_type: 杂志文章,随机对照试验
doi:10.1161/CIRCRESAHA.115.306332
更新日期:2015-08-28 00:00:00
abstract::Rho regulates various cell functions, including cell morphology and motility. However, the functional role of Rho on the signaling pathway in myocardial cells (MCs) is unknown. In the present study, we attempted to explore the mode of Rho action for c-fos gene expression in MCs. Expression of the c-fos promoter/enhanc...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.5.672
更新日期:1997-11-01 00:00:00
abstract::The atrioventricular (AV) node is a recurrent source of potentially life-threatening arrhythmias. Nevertheless, limited data are available on its developmental control or molecular phenotype. We used a novel AV nodal myocardium-specific reporter mouse to gain insight into the gene programs determining the formation an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.192443
更新日期:2009-07-02 00:00:00
abstract::High-density lipoprotein (HDL) is a complex mixture of lipoproteins that is associated with many minor proteins and lipids that influence the function of HDL. Although HDL is a promising marker and potential therapeutic target based on its epidemiological data and the effects of healthy HDL in vitro in endothelial cel...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.114.300935
更新日期:2014-01-03 00:00:00
abstract::Ultrarapid freezing has been applied to monitor the structure of the freeze-fractured myocardial sarcolemma. Our two goals were to demonstrate that large areas of membrane can be preserved free of visible ice crystal damage and, thus, be amenable to quantitative analysis and to compare the structure of directly frozen...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.1.141
更新日期:1987-07-01 00:00:00
abstract::To investigate the possible contributions of cardiac volume overload and cardiac sympathetic hyperactivity in the effects of sodium on cardiac mass, we evaluated the effects of treatment with saline (1%) and deoxycorticosterone acetate + saline (DOCA/saline) for 10 days and 3 and 6 weeks on ventricular anatomy and int...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.3.745
更新日期:1991-03-01 00:00:00
abstract::Genetically hypertensive (GH) rats of the New Zealand strain and normotensive (N) rats were sympathectomized from birth with 6-hydroxydopamine (100 mg/kg,s.c, on alternate days, seven treatments). In adult treated rats from each strain (GHTr and NTr), blood pressure was lower than normal. Functional tests and electron...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.43.2.293
更新日期:1978-08-01 00:00:00
abstract::Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA re...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.2.284
更新日期:1995-02-01 00:00:00
abstract::The vasoactive mechanisms of the serine protease alpha-thrombin were examined in isolated coronary arteries from dogs. In resting coronary arteries with endothelium, alpha-thrombin caused concentration-dependent contractions that were characterized by an initial transient relaxation followed by slowly developing susta...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.5.930
更新日期:1994-05-01 00:00:00
abstract::Body surface electrocardiograms and electrograms recorded from the surfaces of the heart are the basis for diagnosis and treatment of cardiac electrophysiological disorders and arrhythmias. Given recent advances in understanding the molecular mechanisms of arrhythmia, it is important to relate these electrocardiograph...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000016960.61087.86
更新日期:2002-05-03 00:00:00
abstract::Bone morphogenetic protein receptor 2 (BMPR2) mutations have been linked to familial pulmonary arterial hypertension (PAH), but the molecular pathways leading to this severe pathology remain poorly characterized. We report that hypoxia, a paramount stimulus for the development of pulmonary hypertension, suppresses the...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000237021.65103.24
更新日期:2006-08-04 00:00:00
abstract::As early as the 4th embryonic day, the ventricle of the chick embryo responded to isoproterenol (Iso) with an increase in the force of contraction; at all ages studied, this positive inotropic effect was accompanied by an increased rate of tension development. There was a transient, 10-fold decrease in the sensitivity...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.48.2.245
更新日期:1981-02-01 00:00:00
abstract::Cells with endothelial phenotype generated from adult peripheral blood have emerging diagnostic and therapeutic potential. This study examined the lineage relationship between, and angiogenic function of, early endothelial progenitor cells (EPCs) and late outgrowth endothelial cells (OECs) in culture. Culture conditio...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000105569.77539.21
更新日期:2003-11-28 00:00:00
abstract:RATIONALE:Diabetes mellitus increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models, diabetes mellitus impairs atherosclerosis plaque regression after aggressive cholesterol lowering. MicroRNA 33 (miR33) is a key negat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.304164
更新日期:2014-10-10 00:00:00
abstract:RATIONALE:The epicardium contributes to the majority of nonmyocardial cells in the adult heart. Recent studies have reported that the epicardium is derived from Nkx2.5-positive progenitors and can differentiate into cardiomyocytes. Not much is known about the relation between the myocardial and epicardial lineage durin...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.203083
更新日期:2009-08-28 00:00:00
abstract::The role of contracture in the manifestation of calcium paradox-induced damage was examined using 2,3-butanedione monoxime (BDM) to inhibit myofibrillar activity. Calcium and sodium gain, loss of intracellular components, and changes in structure were monitored. If 30 mM BDM was added at the time of calcium repletion ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.4.560
更新日期:1987-10-01 00:00:00
abstract::To isolate specific markers of both differentiated and proliferating vascular smooth muscle cells (VSMCs), we used the technique of differential cDNA screening using RNA from cultured rat aortic VSMCs. The tissue specificity of expression of all of the cDNAs isolated was determined by Northern analysis. We isolated se...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.1.193
更新日期:1993-07-01 00:00:00
abstract::In pentobrabital-anesthetized open chest dogs, myocardial adenosine content is elevated by 5 or 15 seconds of left coronary artery occlusion and falls exponentially to control levels during reactive hyperemia. The rate constants for adenosine dissipation are (mean +/- SEM): -0.08 +/- 0.01 and -0.034 +/- 0.007 sec-1 af...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.42.3.358
更新日期:1978-03-01 00:00:00
abstract::Mechanoreceptors and chemoreceptors have been identified inside the kidney, but their functional role is still largely unclear. The aim of this study was to investigate whether changes in urine output could modify the discharge rate of renal afferent fibers. Experiments were performed in anesthetized cats in which aff...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.5.906
更新日期:1993-11-01 00:00:00
abstract:RATIONALE:Although tyrosine kinases (TKs) are important for cardiac function, their relevant downstream targets in the adult heart are unknown. The ShcA docking protein binds specific phosphotyrosine (pTyr) sites on activated TKs through its N-terminal pTyr-binding (PTB) and C-terminal SH2 domains and stimulates downst...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.233924
更新日期:2011-01-21 00:00:00