In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis

Djamel Lebeche, Roger Kaprielian, Federica Del Monte, Gordon Tomaselli, Judith K. Gwathmey, Arnold Schwartz, Roger J. Hajjar

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Abstract

Background - Prolongation of the action potential duration (APD) and decreased transient outward K+ current (Ito] have been consistently observed in cardiac hypertrophy. The relation between electrical remodeling and cardiac hypertrophy in vivo is unknown. Methods and Results - We studied rat hearts subjected to pressure overload by surgical ascending aortic stenosis (AS) and simultaneously infected these hearts with an adenovirus carrying either the Kv4.3 gene (Ad.Kv4.3) or the β-galactosidase gene (Ad.β-gal). Ito density was reduced and APD50 was prolonged (P<0.05) in AS rats compared with sham rats. Kv4.2 and Kv4.3 expressions were decreased by 58% and 51%, respectively (P<0.05). AS rats infected with Ad.β-gal developed cardiac hypertrophy compared with sham rats, as assessed by cellular capacitance and heart weight-body weight ratio. Associated with the development of cardiac hypertrophy, the expression of calcineurin and its downstream transcription factor nuclear factor of activated T cells (NFAT) c1 was persistently increased by 47% and 36%, respectively (P<0.05) in AS myocytes infected with Ad.β-gal compared with sham myocytes. In vivo gene transfer of Kv4.3 in AS rats was shown to increase Kv4.3 expression, increase Ito density, and shorten APD50 by 1.6-fold, 5.3-fold, and 3.6-fold, respectively (P<0.05). Furthermore, AS rats infected with Ad.Kv4.3 showed significant reductions in calcineurin and NFAT expression. (P<0.05). Conclusions - Downregulation of Ito, APD prolongation, and cardiac hypertrophy occur early after AS, and in vivo gene transfer of Kv4.3 can restore these electrical parameters and abrogate the hypertrophic response via the calcineurin pathway.

Original languageEnglish (US)
Pages (from-to)3435-3443
Number of pages9
JournalCirculation
Volume110
Issue number22
DOIs
Publication statusPublished - Nov 30 2004
Externally publishedYes

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Keywords

  • Gene therapy
  • Hypertrophy
  • Ion channels
  • Potassium
  • Stenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lebeche, D., Kaprielian, R., Del Monte, F., Tomaselli, G., Gwathmey, J. K., Schwartz, A., & Hajjar, R. J. (2004). In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis. Circulation, 110(22), 3435-3443. https://doi.org/10.1161/01.CIR.0000148176.33730.3F