Molecular remodeling of cardiac contractile function

Abstract

A number of techniques are now available that allow the contractile apparatus of the heart to be altered in a defined manner. This review focuses on those approaches that result in germ-line transmission of the remodeling event(s). Thus the desired modifications can be propagated stably throughout multiple generations and result in the creation of stable, new animal models. Necessarily, such stable changes need to be performed at the level of the genome, and two distinct but complementary approaches have been developed: transgenesis and gene targeting. Each results in the stable modification of the mammalian genome. Via gene targeting or gene ablation of sequences encoding various components of the sarcomere, the contractile apparatus of the heart can be altered dramatically. Ablating a gene may lead to a loss in function, which can help establish a function of the candidate sequence. Gene targeting can also be used to effect changes in the sequences encoding a functional domain of the contractile protein or at a single-amino acid residue, resulting in the establishment of precise structure-function relationships. With the use of transgenesis, the contractile apparatus of the heart can also be significantly remodeled. These approaches are rapidly creating a group of animals in which altered contractile protein complements will lead to a fundamental understanding of the structure-function relationships that underlie the function of the heart at the molecular, biochemical, whole organ, and whole animal levels.