Cardiac performance in systole and diastole is critically dependent on the underlying kinetics of the cross-bridge cycle. In several small mammalian species, these kinetics are determined by the myosin heavy chain (MHC) isomer. Such a control mechanism is not available in the human heart, where dramatic change's in cross-bridge kinetics occur under hypertrophy and failure conditions with essentially no change in MHC isoform. The mechanism behind this alternative control pathway is unknown. A similar situation occurs in response to right ventricular pressure overload in the rabbit, where large changes in cross-bridge kinetics are accompanied by very subtle shifts in MHC. The hemodynamically stressed rabbit thus offers an exceptional animal model for the study of non-MHC dependent alterations in cardiac cross-bridge cycling kinetics. One goal of these proposed experiments is to dissect the cross-bridge cycle using a blend of mechanical and biochemical measurements. Important kinetic parameters such as cross-bridge attachment, detachment and cycling rates will be obtained in control and pressure overload rabbits, as well as a third model of cardiac atrophy which mimics the slight shift in MHC seen in pressure overload. These data will indicate exactly how the cross-bridge cycle changes under cardiac hypertrophy. Another goal is to elucidate the mechanisms responsible for these kinetic changes. Specific candidates are myosin light chain phosphorylation or cleavage, as well as isoform shifts in troponin T. A knowledge of these fundamental control mechanisms and their effect on the cross-bridge cycle is crucial to understanding and treating the hemodynamically stressed heart.
| Peterson, J N; Nassar, R; Anderson, P A et al. (2001) Altered cross-bridge characteristics following haemodynamic overload in rabbit hearts expressing V3 myosin. J Physiol 536:569-82 |
| Peterson, J N; Alpert, N R (1998) Cross-bridge dynamics in the contracting heart. Adv Exp Med Biol 453:117-23;discussion 123-4 |
| Peterson, J N; Alpert, N R (1996) Molecular motor mechanics in the contracting heart. V1 versus V3 myosin heavy chain. Ann N Y Acad Sci 793:54-63 |
