title: Impaired sarcoplasmic reticulum function leads to contractile dysfunction and cardiac hypertrophy.
abstract: Sarcoplasmic reticulum (SR)-mediated Ca(2+) sequestration and release are important determinants of cardiac contractility. In end-stage heart failure SR dysfunction has been proposed to contribute to the impaired cardiac performance. In this study we tested the hypothesis that a targeted interference with SR function can be a primary cause of contractile impairment that in turn might alter cardiac gene expression and induce cardiac hypertrophy. To study this we developed a novel animal model in which ryanodine, a substance that alters SR Ca(2+) release, was added to the drinking water of mice. After 1 wk of treatment, in vivo hemodynamic measurements showed a 28% reduction in the maximum speed of contraction (+dP/dt(max)) and a 24% reduction in the maximum speed of relaxation (-dP/dt(max)). The slowing of cardiac relaxation was confirmed in isolated papillary muscles. The late phase of relaxation expressed as the time from 50% to 90% relaxation was prolonged by 22%. After 4 wk of ryanodine administration the animals had developed a significant cardiac hypertrophy that was most prominent in both atria (right atrium +115%, left atrium +100%, right ventricle +23%, and left ventricle +13%). This was accompanied by molecular changes including a threefold increase in atrial natriuretic factor mRNA and a sixfold increase in beta-myosin heavy chain mRNA. Sarcoplasmic endoplasmic reticulum Ca(2+) mRNA was reduced by 18%. These data suggest that selective impairment of SR function in vivo can induce changes in cardiac gene expression and promote cardiac growth.
authors: Department of Medicine, University of California, San Diego, California 92093, USA.
authors: M
authors: M
authors: Meyer
authors: S U
authors: SU
authors: Trost
authors: W F
authors: WF
authors: Bluhm
authors: H J
authors: HJ
authors: Knot
authors: E
authors: E
authors: Swanson
authors: W H
authors: WH
authors: Dillmann
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB; D009929:Organ Size; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D002316:Cardiotonic Agents; D012433:Ryanodine; D009320:Atrial Natriuretic Factor; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium