Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2 transients and arrhythmias associated with cardiac hypertrophy

Dagmar Harzheim; Mehregan Movassagh; Roger S.-Y.FooOliver RitterAslam TashfeenStuart J.ConwayMartin D. BootmanH.Llewelyn Roderick

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Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2 transients and arrhythmias associated with cardiac hypertrophy

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Cardiac hypertrophy is a growth response of the heart to increasedhemodynamic demand or damage.Accompanying this heart enlargementis a remodeling of Ca2 signaling.Due to its fundamental rolein controlling cardiomyocyte contraction during every heartbeat,modifications in Ca2 fluxes significantly impact on cardiac outputand facilitate the development of arrhythmias.Using cardiomyocytesfrom spontaneously hypertensive rats(SHRs),we demonstrate thatan increase in Ca2release through inositol 1,4,5-trisphosphate receptors(InsP3Rs)contributes to the larger excitation contractioncoupling(ECC)-mediated Ca2 transients characteristic of hypertrophicmyocytes and underlies the more potent enhancement of ECCmediatedCa2 transients and contraction elicited by InsP3 or endothelin-1(ET-1).Responsible for this is an increase in InsP3R expressionin the junctional sarcoplasmic reticulum.Due to their close proximityto ryanodine receptors(RyRs)in this region,enhanced Ca2 releasethrough InsP3Rs served to sensitize RyRs,thereby increasing diastolicCa2levels,the incidence of extra-systolic Ca2 transients,and theinduction of ECC-mediated Ca2 elevations. Unlike the increase inInsP3R expression and Ca2 transient amplitude in the cytosol, InsP3Rexpression and ECC-mediated Ca2 transients in the nucleus were notaltered during hypertrophy. Elevated InsP3R2 expression was alsodetected in hearts from human patients with heart failure afterischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophicmouse hearts. Our data establish that increased InsP3R expressionis a general mechanism that underlies remodeling of Ca2signaling during heart disease, and in particular, in triggering ventriculararrhythmia during hypertrophy.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2009年第27期|11406-11411|共6页
作者
Dagmar Harzheim; Mehregan Movassagh; Roger S.-Y.FooOliver RitterAslam TashfeenStuart J.ConwayMartin D. BootmanH.Llewelyn Roderick;
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作者单位

Department of Molecular Signaling, Babraham Institute, Cambridge, CB22 3AT, United Kingdom;

Addenbrooke__s Centre for Clinical Investigation,Cambridge, CB2 0QQ, United Kingdom;

Department of Medicine I, University of Wuerzburg, 97080 Wuerzburg, GermanyDepartment of Chemistry,University of St.Andrews,St. Andrews,KY16 9ST,United KingdomDepartment of Chemistry,University of Oxford, Oxford,OX1 3TA,United KingdomDepartment of Molecular Signaling,Babraham Institute,Cambridge,CB223AT,United Kingdom;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
hypertrophy; cardiomyocyte; arrhythmia;

Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2 transients and arrhythmias associated with cardiac hypertrophy

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