Published online before print June 7, 2007, doi: 10.1161/CIRCRESAHA.107.155721
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Submitted on December 21, 2006
Revised on May 10, 2007
Accepted on May 30, 2007
Gene Therapy to Inhibit the Calcium Channel 
Subunit. Physiological Consequences and Pathophysiological Effects in Models of Cardiac Hypertrophy
Eugenio Cingolani ;
From the Division of Cardiology (E.C., G.A.R.C., E.K., M.M., H.C.C., E.M.), Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: marban{at}jhmi.edu.
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 
-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 -subunit gene was incorporated into a lentiviral vector (PPT.CG.H1.2). 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 -subunit gene knockdown reduced calcium transient amplitude. Similarly, [3H]leucine incorporation was attenuated in PPT.CG.H1.2-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.H1.2-injected rats at four weeks post transduction. Fractional shortening was preserved in rats treated with PPT.CG.H1.2. These findings indicate that knockdown of L-type calcium channel accessory -subunit is capable of attenuating the hypertrophic response both in vitro and in vivo without compromising systolic performance. Suppression of the calcium channel subunit may represent a novel and useful therapeutic strategy for left ventricular hypertrophy.
Key words: hypertrophy • calcium • gene therapy
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