Genetic manipulation of calcium-handling proteins in cardiac myocytes. I. Experimental studies

Pierre Coutu, Joseph M. Metzger

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Two genetic experimental approaches, de novo expression of parvalbumin (Parv) and overexpression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), have been shown to increase relaxation rates in myocardial tissue. However, the relative effect of Parv and SERCA2a on systolic function and on β-adrenergic responsiveness at varied pacing rates is unknown. We used gene transfer in isolated rat adult cardiac myocytes to gain a fuller understanding of Parv/SERCA2a function. As demonstrated previously, when Parv is expressed in elevated concentration (>0.1 mM), the transduced myocytes showed a reduction in sarcomere-shortening amplitude: 129 ± 17, 81 ± 8, and 149 ± 14 nm for control, Parv, and SERCA2a, respectively. At physiological temperature, shortening amplitude responses of Parv and SERCA2a myocytes to the β-adrenergic agonist isoproterenol (Iso) were not statistically different from that of control myocytes. However, in SERCA2a myocytes, in which baseline was slightly elevated and the Iso-stimulated value was slightly lower, the increase in shortening was slightly less than in Parv or control myocytes: 108 ± 14, 169 ± 39, and 34 ± 12% for control, Parv, and SERCA2a, respectively. In another test set, Parv myocytes had the strongest early postrest potentiation among all groups studied (rest time = 2-10 s), and SERCA2a myocytes were the least sensitive to variations in stimulation rhythm. To replicate the deficient Ca2+ removal observed in heart failure, we used 150 nM thapsigargin. Under these conditions, control myocytes exhibited slowed relaxation, whereas Parv myocytes retained their rapid kinetics, showing that Parv is still able to control relaxation, even when SERCA2a function is impaired.

Original languageEnglish (US)
Pages (from-to)H601-H612
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number2 57-2
DOIs
StatePublished - Feb 2005

Keywords

  • Diastolic dysfunction
  • Gene transfer
  • Parvalbumin
  • Postrest potentiation
  • Sarco(endo)plasmic reticulum calcium-adenosinetri-phosphatase 2a
  • Thapsigargin

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