Impaired sarcoplasmic reticulum function leads to contractile dysfunction and cardiac hypertrophy

Markus Meyer, Susanne U. Trost, Wolfgang F. Bluhm, Harm J. Knot, Eric Swanson, Wolfgang H. Dillmann

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Sarcoplasmic reticulum (SR)-mediated Ca2+ 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 Ca2+ 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/dtmax) and a 24% reduction in the maximum speed of relaxation (-dP/dtmax). 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 artrium +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 β-myosin heavy chain mRNA. Sarcoplasmic endoplasmic reticulum Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)H2046-H2052
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number5 49-5
StatePublished - May 1 2001
Externally publishedYes

Keywords

  • Ca handling
  • Endothelial cell coupling
  • Growth
  • Inotropic agents
  • Myocardial contraction

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