Gene therapy to inhibit the calcium channel β subunit: Physiological consequences and pathophysiological effects in models of cardiac hypertrophy

Eugenio Cingolani, Genaro A.Ramirez Correa, Eddy Kizana, Mitsushige Murata, Hee Cheol Cho, Eduardo Marbán

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Calcium cycling figures prominently in excitation-contraction coupling and in various signaling cascades involved in the development of left ventricular hypertrophy. We hypothesized that genetic suppression of the L-type calcium channel accessory β-subunit would modulate calcium current and suppress cardiac hypertrophy. A short hairpin RNA template sequence capable of mediating the knockdown of the L-type calcium channel accessory β-subunit gene was incorporated into a lentiviral vector (PPT.CG.H1.β2). Transduction of ventricular myocytes in vivo with the active short hairpin RNA partially inhibited the L-type calcium current. In neonatal rat cardiomyocytes, L-type calcium channel accessory β-subunit gene knockdown reduced calcium transient amplitude. Similarly, [H]leucine incorporation was attenuated in PPT.CG.H1.β2-transduced neonatal rat cardiomyocytes compared with nonsilencing controls in a phenylephrine-induced hypertrophy model. In vivo gene transfer attenuated the hypertrophic response in an aortic-banded rat model of left ventricular hypertrophy, with reduced left ventricular wall thickness and heart weight/body weight ratios in PPT.CG.H1.β2-injected rats at four weeks post transduction. Fractional shortening was preserved in rats treated with PPT.CG.H1.β2. These findings indicate that knockdown of L-type calcium channel accessory β-subunit is capable of attenuating the hypertrophic response both in vitro and in vivo without compromising systolic performance. Suppression of the calcium channel β subunit may represent a novel and useful therapeutic strategy for left ventricular hypertrophy.

Original languageEnglish
Pages (from-to)166-175
Number of pages10
JournalCirculation research
Volume101
Issue number2
DOIs
Publication statusPublished - 2007 Jul 1

Keywords

  • Calcium
  • Gene therapy
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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