Abstract:
BACKGROUND:Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere. OBJECTIVES:The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM. METHODS:Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (Mypn(WT/Q526X)) and homozygote mice harboring the human MYPN-Q529X mutation. RESULTS:Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated Mypn(Q526X) protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers. CONCLUSIONS:Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in Mypn(WT/Q526X) hearts.
journal_name
J Am Coll Cardioljournal_title
Journal of the American College of Cardiologyauthors
Huby AC,Mendsaikhan U,Takagi K,Martherus R,Wansapura J,Gong N,Osinska H,James JF,Kramer K,Saito K,Robbins J,Khuchua Z,Towbin JA,Purevjav Edoi
10.1016/j.jacc.2014.09.071subject
Has Abstractpub_date
2014-12-30 00:00:00pages
2765-76issue
25eissn
0735-1097issn
1558-3597pii
S0735-1097(14)06749-7journal_volume
64pub_type
杂志文章abstract:OBJECTIVE:We studied the effects of sildenafil, a phosphodiesterase 5 inhibitor, on coronary and peripheral vascular function, platelet activation, and myocardial ischemia. BACKGROUND:Nitric oxide vasodilates and inhibits platelet activation by generating cyclic guanosine 5'-monophosphate, which is metabolized by phos...
journal_title:Journal of the American College of Cardiology
pub_type: 临床试验,杂志文章,随机对照试验
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abstract:OBJECTIVES:We investigated whether abnormal pteridine metabolism is related to coronary endothelial dysfunction in insulin-resistant subjects. BACKGROUND:Depletion of tetrahydrobiopterin (BH(4)) and elevation of the 7,8-dihydrobiopterin (BH(2)) (activating and inactivating cofactors of nitric oxide synthase [NOS], res...
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更新日期:2001-12-01 00:00:00
abstract::Percutaneous balloon valvuloplasty was attempted in 10 newborn infants with critical aortic valve stenosis and severe congestive heart failure. Three had a very small left ventricle and aortic anulus. In one infant, the aortic valve could not be passed, and in another infant, a technical error resulted in severe valvu...
journal_title:Journal of the American College of Cardiology
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doi:10.1016/0735-1097(89)90268-4
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abstract:OBJECTIVES:The purpose of this study was to design a more efficient protocol for the electrical cardioversion of atrial arrhythmias. BACKGROUND:Guidelines for electrical cardioversion of atrial arrhythmias recommend starting with low energy shocks, which are often ineffective. METHODS:We recorded the sequence of shoc...
journal_title:Journal of the American College of Cardiology
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journal_title:Journal of the American College of Cardiology
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更新日期:2012-11-06 00:00:00
abstract:OBJECTIVES:This registry collected the 30-day and 9-month clinical outcomes of patients whose coronary stent implantation was suboptimal, and compared them with the cohort of patients with "optimal" stenting in the randomized portion of the STent Anti-thrombotic Regimen Study (STARS) trial. BACKGROUND:Although "optima...
journal_title:Journal of the American College of Cardiology
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更新日期:1999-09-01 00:00:00
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journal_title:Journal of the American College of Cardiology
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更新日期:2016-08-09 00:00:00
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更新日期:2014-03-25 00:00:00
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更新日期:1985-05-01 00:00:00
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journal_title:Journal of the American College of Cardiology
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更新日期:2005-01-18 00:00:00
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journal_title:Journal of the American College of Cardiology
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更新日期:2013-07-09 00:00:00
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更新日期:2007-01-23 00:00:00
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更新日期:2017-07-18 00:00:00
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journal_title:Journal of the American College of Cardiology
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更新日期:1999-05-01 00:00:00
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更新日期:2014-01-28 00:00:00
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journal_title:Journal of the American College of Cardiology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2000-01-01 00:00:00
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更新日期:2001-03-01 00:00:00
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更新日期:2004-03-17 00:00:00
abstract::To test the value of acceleration flow signals proximal to the leaking orifice in assessing the severity of prosthetic mitral valve regurgitation, 39 consecutive patients undergoing left ventriculography were examined by Doppler color flow imaging. Acceleration flow signals proximal to the regurgitant orifice were det...
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pub_type: 杂志文章
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更新日期:1992-02-01 00:00:00