Molecular phenotype of the hypertrophied and failing myocardium

Abstract

Hemodynamic overload produces in the cardiac myocyte a complex pattern of gene reprogramming, a 'mechanogenic transduction,' characterized by qualitative and quantitative changes of gene expression. The qualitative changes involve differential expression of multigene families of contractile proteins, especially myosin heavy chain and actin, but until now, most attention has been focused on myosin heavy chain isogenes. Our recent studies were designed to characterize the pattern of expression of sarcomeric isoactins and to determine whether there is a common regulatory pathway between myosin heavy chain and actin genes. For this, we have analyzed the respective mRNA levels of α-skeletal and α-cardiac actins in human and rat ventricles during ontogeny, senescence, hypertrophy, and failure. We found that both actin isogenes are always coexpressed but that the pattern is species specific and changes depending on the situation. In man, α-skeletal actin is upregulated during development and is the predominant isoform of young and adult hearts. In rat, in contrast, α-skeletal actin is downregulated 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 pattern as the control ones. Comparison of all the above results with those previously reported for α- and β-myosin heavy chains indicate that myosin heavy chain and actin multigene families both are expressed in a species-specific fashion and that they are independently regulated. 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 transcriptional. It also appears that the transcriptional activities of the individual genes are modified during postnatal development. Quantitative changes with hemodynamic overload involve a relative decrease in the expression, without an isoform switch, of the main enzyme responsible for relaxation, the sarco(endo)plasmic reticulum ATPase, which can account, at least in part, for the alterations of calcium movements and relaxation in the hypertrophied heart. We have studied expression of this gene during the life span of rats and found that it is upregulated after birth and downregulated during aging. The overall pattern that emerges from these studies is that cardiac hypertrophy and growth, whatever the animal species, are accompanied by a very complex modulation of the genes responsible for contraction and relaxation and that it is now possible to determine the regulational level of cardiac gene expression, which should facilitate our understanding of the molecular mechanisms that result in a given phenotype and why they become ineffective during heart failure.