Adenoviral gene transfer of mutant phospholamban rescues contractile dysfunction in failing rabbit myocytes with relatively preserved SERCA function

Mark T. Ziolo, Jody L. Martin, Julie B C Bossuyt, Donald M Bers, Steven M. Pogwizd

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In heart failure (HF) a main factor in reduced contractility is reduced SR Ca2+ content and reversed force-frequency response (FFR), ie, from positive to negative. Our arrhythmogenic rabbit HF model exhibits decreased contractility mainly due to an increase in Na/Ca exchange (NCX) activity (with only modest decrease in SR Ca2+-ATPase (SERCA) function), similar to many end-stage HF patients. Here we test whether phospholamban (PLB) inhibition using a dominant-negative mutant PLB adenovirus (K3E/R14E, AdPLB-dn, with β-galactosidase adenovirus as control) could enhance SERCA function and restore Ca2+ transients and positive FFR in ventricular myocytes from these HF rabbits. HF myocytes infected with AdPLB-dn (versus control) had enhanced Ca2+ transient amplitude (2.0±0.1 versus 1.6±0.05 F/Fo at 0.5 Hz, P<0.05) and had a positive FFR, whereas acutely isolated HF myocytes or those infected with Adβgal had negative FFR. Ca2+ transients declined faster in AdPLB-dn versus Adβgal myocytes (RT50%: 317±29 versus 551±90 ms at 0.5 Hz, P<0.05) and had an increased SR Ca2+ load (3.5±0.3 versus 2.6±0.2 F/Fo at 0.5 Hz, P<0.05), indicative of increased SERCA function. Furthermore, this restoration of function was not due to changes in NCX or SERCA expression. Thus, increasing SERCA activity in failing myocytes by AdPLB-dn gene transfer reversed the contractile dysfunction (and restored positive FFR) by increasing SR Ca2+ load. This approach could enhance contractile function in failing hearts of various etiologies, even here where reduced SERCA activity is not the main dysfunction.

Original languageEnglish (US)
Pages (from-to)815-817
Number of pages3
JournalCirculation Research
Volume96
Issue number8
DOIs
StatePublished - Apr 29 2005
Externally publishedYes

Keywords

  • Gene transfer
  • Heart failure
  • Phospholamban
  • SERCA

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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