Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart

Abstract

The physiology of myocardial contractility has been studied for over a century, but only recently has molecular biology provided new insights into the mechanisms responsible for the alterations of contraction and relaxation observed during cardiac hypertrophy and heart failure. Pressure and volume overload produce in the myocyte both qualitative changes characterized by protein isoform switches and quantitative changes characterized by modulation of single genes through a mechanogenic transduction the pathways of which are largely unknown. The qualitative changes involve differential expression of multigene families of contractile proteins, especially myosin heavy chain (MHC) and actin. All situations of pressure overload, or of combined pressure and volume overload activate the β-MHC gene and deactivate the α-MHC one, which leads to a slower, more efficient contraction. In rat, pressure overload transitorily activates the α-skeletal actin gene, and both the timing and the distribution of the newly formed β-MHC and α-skeletal actin mRNAs differ. We recently found that the isoactin pattern is the same in patients with end-stage heart failure as that of control human hearts. Moreover, both in rat and human, expression of isomyosins and isoactins are not coordinated, neither during ontogeny nor senescence. All this suggests the existence of several regulatory mechanisms activated during normal cardiac growth or by a mechanical trigger, and preliminary results indicate that it is possible to perform nuclear run-on assays in order to analyze the transcriptional step of these isogenes. Relaxation of the hypertrophied heart is characterized by a relative decrease in the activity of the gene coding for the sarco(endo)plasmic reticulum ATPase (SERCA), both in rat and in man, which can explain some of the alterations of calcium handling by the hypertrophied myocyte. In conclusion, reprogramming of cardiac gene expression during ontogeny and chronic hemodynamic overloading is a complex phenomenon, and it could be hypothesized that further exploration of these genetic events may enable us to better understand how cardiac function is regulated, both in health and in disease.