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

Abstract

Background-The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), ␣-MHC and ␤-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 ␤-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 ␤-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 ␤-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 ϮdP/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.

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…A similar conclusion has been drawn from studies with transgenic rabbit hearts, in which nearly 40% of endogenous βMHC was replaced by the αMHC isoform [6]. James et al have reported that the transgenic expression of the αMHC isoform in rabbit hearts has no apparent detrimental effects under basal conditions, and that these hearts are protected against tachycardia-induced cardiomyopathy [6].…”

“…In a study utilizing a single cell system, Herron et al demonstrated that cardiac myocytes expressing only 12% of the αMHC isoform produced a 52% greater power output than did those expressing only the βMHC isoform [25,110]. As mentioned above, results obtained from transgenic rabbits, which have an MHC profile very similar to that of man, have indicated that hearts in which βMHC was replaced by 40% of αMHC were at an advantage under stress conditions in maintaining heart function [6]. This study also ruled out the possibility that decreased αMHC during human heart failure could be a compensatory mechanism for preserving the energy efficiency of the heart.…”

“…James et al have reported that the transgenic expression of the αMHC isoform in rabbit hearts has no apparent detrimental effects under basal conditions, and that these hearts are protected against tachycardia-induced cardiomyopathy [6]. Based on differences in the ATP requirement of two isoforms, it is generally considered that hearts expressing mostly βMHC are more economical, than are hearts expressing mainly αMHC.…”

“…This study also ruled out the possibility that decreased αMHC during human heart failure could be a compensatory mechanism for preserving the energy efficiency of the heart. Because, if this was the case then rabbit hearts with 40% αMHC would have fared worse under stress conditions than the nontransgenic control; obviously this did not happen [6].…”

“…Examination of different biophysical and biochemical parameters has revealed that a shift in the myosin-isoform distribution and a change in the cross bridge cycling characteristics of the sarcomere play a significant role in controlling the shortening velocity of cardiac muscle fibers [2][3][4]. With recent evidence confirming the presence of αMHC in human hearts and its disappearance in failing hearts, a new interest has arisen among investigators in finding ways of restoring and/or up-regulating the αMHC expression in the overloaded heart [5][6][7][8]. The basic premise is that reduction of cardiac hypertrophy combined with increased activity of αMHC could be beneficial in terms of increasing the myocardial contractility of a hemodynamically challenged heart [9].…”