EMBRYONIC GENE-EXPRESSION IN NONOVERLOADED VENTRICLES OF HEREDITARY HYPERTROPHIC CARDIOMYOPATHIC HAMSTERS

Current information regarding the molecular and biochemical mechanisms of myocardial hypertrophy, as obtained from isolated cardiomyocytes a nd/or healthy animals with aortic banding, does not permit dissection of the hierarchical relationship among different steps and triggers of the pathogenic process in vivo. The aim of the present study was to d epict the temporal relationship among myocardial structural and functi onal characteristics, the embryonic gene program, and transforming gro wth factor (TGF)beta 1 expression in euthyroid hereditary hypertrophic cardiomyopathic hamsters (CMPH). This investigation was performed usi ng Western and Northern blot and in situ hybridization techniques. The results show that in CMPH, the severity of the hemodynamic overload i s not related to any modification in structural myocardial characteris tics (cardiac mass, cardiomyocyte dimensions, total RNA, and protein c ontent), whereas an early activation of the embryonic gene program occ urs in not yet overloaded 90-day-old CMPH (left ventricular end diasto lic pressure < 15 mm Hg). In these animals, a 30% to 90% decrease in t he or myosin heavy chain (alpha MHC) relative content was found in ven tricles, whereas beta MHC increased 5-fold. In addition, the oc skelet al actin expression was enhanced 2-fold versus age-matched controls. N o modifications were observed in myosin function evaluated by in vitro motility assay, whereas the administration of L-thyroxine (100 mu g/k g intraperitoneally daily) to CMPH was able to reinduce the ventricula r expression of the alpha MHC isoform (5-fold increase). Conversely, n o changes were found in Lu cardiac actin and myosin light chain 2 (MLC 2) expression. A close temporal relationship occurred in CMPH ventricl es between the re-expression of the embryonic gene program and a 3-fol d enhancement of the expression of TGF beta 1. These results indicate that the CMPH provides a useful model for investigating the expression of embryonic genes in hypertrophic ventricles in the absence of mecha nical and hormonal stimuli, and that TGF beta 1 is involved in regulat ing in vivo the ''embryonic step'' of myocardial hypertrophy. Furtherm ore, the study offers new insights into the pathophysiologic mechanism s leading to heart failure.