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

54 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
Externally publishedYes

Fingerprint

Cardiomegaly
Calcium Channels
L-Type Calcium Channels
Genetic Therapy
Left Ventricular Hypertrophy
Calcium
Cardiac Myocytes
Small Interfering RNA
Genetic Suppression
Gene Knockdown Techniques
Excitation Contraction Coupling
Phenylephrine
Leucine
Muscle Cells
Hypertrophy
Genes
Body Weight
Weights and Measures

Keywords

  • Calcium
  • Gene therapy
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gene therapy to inhibit the calcium channel β subunit : Physiological consequences and pathophysiological effects in models of cardiac hypertrophy. / Cingolani, Eugenio; Correa, Genaro A Ramirez; Kizana, Eddy; Murata, Mitsushige; Cho, Hee Cheol; Marbán, Eduardo.

In: Circulation Research, Vol. 101, No. 2, 07.2007, p. 166-175.

Research output: Contribution to journalArticle

Cingolani, Eugenio ; Correa, Genaro A Ramirez ; Kizana, Eddy ; Murata, Mitsushige ; Cho, Hee Cheol ; Marbán, Eduardo. / Gene therapy to inhibit the calcium channel β subunit : Physiological consequences and pathophysiological effects in models of cardiac hypertrophy. In: Circulation Research. 2007 ; Vol. 101, No. 2. pp. 166-175.
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