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(Circulation. 2005;111:2339-2346.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Forced Expression of -Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions

Jeanne James, MD; Lisa Martin, AS; Maike Krenz, MD; Carmen Quatman, BS; Fred Jones, MD; Raisa Klevitsky, MD; James Gulick, MS; Jeffrey Robbins, PhD

From the Divisions of Molecular Cardiovascular Biology (J.J., L.M., M.K., C.Q., R.K., J.G., J.R.) and Pediatric Cardiology (F.J.), Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to Jeffrey Robbins, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}cchmc.org

Received September 3, 2004; revision received December 7, 2004; accepted January 10, 2005.

Background— The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), -MHC and ß-MHC, are well described, but the physiological consequences of basal isoform expression and isoform shifts in response to altered cardiac load are not clearly understood. Mature human ventricle contains primarily the ß-MHC isoform. However, the -MHC isoform can be detected in healthy human ventricle and appears to be significantly downregulated in failing hearts. The unique biochemical properties of the -MHC isoform might offer functional advantages in a failing heart that is expressing only the ß-MHC isoform. This hypothesis cannot be tested in mice or rats because both species express -MHC as the predominant isoform.

Methods and Results— To test the effects of persistent -MHC expression on the background of ß-MHC, we made transgenic (TG) rabbits that expressed rabbit -MHC cDNA in the ventricle so that the endogenous myosin was partially replaced by the transgenically encoded species. Molecular, histological, and functional analyses showed no significant baseline effects in the TG rabbits compared with nontransgenic (NTG) littermates. To determine whether -MHC expression afforded any advantages to stressed myocardium, a cohort of TG and NTG rabbits was subjected to rapid ventricular pacing. Although both the TG and NTG rabbits developed dilated cardiomyopathy, the TG rabbits had a higher shortening fraction, less septal thinning, and more normal ±dP/dt than paced NTG rabbits.

Conclusions— Transgenic expression of -MHC does not have any apparent detrimental effects under basal conditions and is cardioprotective in experimental tachycardia-induced cardiomyopathy.

Key Words: cardiomyopathy • heart failure • molecular biology • myocardial contraction

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