Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction

Jennifer C. Hirsch, Andrea R. Borton, Faris P. Albayya, Mark W. Russell, Richard G. Ohye, Joseph M. Metzger

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike diastolic dysfunction was established through 1 yr of left ventricular (LV) pressure overload by descending thoracic aortic coarctation in canines. Serial echocardiography documented a progressive increase in LV mass. Diastolic dysfunction with preserved systolic function was evident at the whole organ and myocyte levels in this model, as determined by hemispheric sonomicrometric piezo-electric crystals, pressure transducer catheterization, and isolated myocyte studies. Gene transfer of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) and parvalbumin (Parv), a fast-twitch skeletal muscle Ca2+ buffer, restored cardiac myocyte relaxation in a dose-dependent manner under baseline conditions. At high Parv concentrations, sarcomere shortening was depressed. In contrast, during β-adrenergic stimulation, the expected enhancement of myocyte contraction (inotropy) was abrogated by SERCA2a but not by Parv. The mechanism of this effect is unknown, but it could relate to the uncoupling of SERCA2a/phospholamban in SERCA2a myocytes. Considering that inotropy is vital to overall cardiac performance, the divergent effects of SERCA2a and Parv reported here could impact potential therapeutic strategies for human heart failure.

Original languageEnglish (US)
Pages (from-to)H2314-H2321
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume286
Issue number6 55-6
DOIs
StatePublished - Jun 2004

Keywords

  • Calcium
  • Canine
  • Contraction
  • Heart failure
  • Inotropy
  • Sarco(endo)plasmic reticulum Ca-ATPase 2a

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