MOLECULAR PHENOTYPE OF THE HYPERTROPHIED AND FAILING MYOCARDIUM

Hemodynamic overload produces in the cardiac myocyte a complex pattern of gene reprogramming, a ''mechanogenic transduction,'' characterized by quatitative and quantitative changes of gene expression. The quali tative changes involve differential expression of multigene families o f contractile proteins, especially myosin heavy chain and actin, but u ntil now, most attention has been focused on myosin heavy chain isogen es. Our recent studies were designed to characterize the pattern of ex pression of sarcomeric isoactins and to determine whether there is a c ommon regulatory pathway between myosin heavy chain and actin genes. F or this, we have analyzed the respective mRNA levels of alpha-skeletal and alpha-cardiac actins in human and rat ventricles during ontogeny, senescence, hypertrophy, and failure. We found that both actin isogen es are always coexpressed but that the pattern is species specific and changes depending on the situation. In man, alpha-skeletal actin is u pregulated during development and is the predominant isoform of young and adult hearts. In rat, in contrast, alpha-skeletal actin is downreg ulated during development and after 2 months of age is expressed at a low level that does not change in aged animals. Explanted hearts from patients with end-stage heart failure exhibited the same isoactin patt ern as the control ones. Comparison of all the above results with thos e previously reported for alpha- and beta-myosin heavy chains indicate that myosin heavy chain and actin multigene families both am expresse d in a species-specific fashion and that they are independently regula ted. We have set up a run-on assay to analyze the level of regulation, transcriptional, posttranscriptional, or both, of these isogenes in 3 -week-old rats and have found that their regulation is primarily trans criptional. It also appears that the transcriptional activities of the individual genes are modified during postnatal development. Quantitat ive changes with hemodynamic overload involve a relative decrease in t he expression, without an isoform switch, of the main enzyme responsib le for relaxation, the sarco(endo)plasmic reticulum ATPase, which can account, at least in part, for the alterations of calcium movements an d relaxation in the hypertrophied heart. We have studied expression of this gene during the life span of rats and found that it is upregulat ed after birth and downregulated during aging. The overall pattern tha t emerges from these studies is that cardiac hypertrophy and growth, w hatever the animal species, are accompanied by a very complex modulati on of the genes responsible for contraction and relaxation and that it is now possible to determine the regulational level of cardiac gene e xpression, which should facilitate our understanding of the molecular mechanisms that result in a given phenotype and why they become ineffe ctive during heart failure.