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Embryonic
Gene Expression in Nonoverloaded Ventricles of Hereditary Hypertrophic Cardiomyopathic
Hamsters |
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Paolo Di Nardo,
Roberta Fiaccavento, Angelo Natali, Marilena Minieri, Maurilio Sampaolesi,
Angelo Fusco, Chantal Janmot, Giovanni Cuda, Arnaldo Carbone, Paola Rogliani,
and Giuseppe Peruzzi |
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Laboratorio
di Cardiologia Molecolare e Cellulare, Dipartimento di Medicina Interna,
Universita di Roma ``Tor Vergata'' (PDN, RF, AN, MM, MS, AF, PR, GP), Roma,
Italy; Unit|f4 de Recherche Associ|fee Centre National de la Recherche Scientifique
1131 (CJ), Universite Paris-Sud, Orsay, France; and Dipartimento di Medicina
Sperimentale e Clinica (GC), Universita di Reggio Calabria, Catanzaro, and
Istituto di Anatomia Patologica (AC), Universita Cattolica, Roma, Italy |
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Current information regarding
the molecular and biochemical mechanisms of myocardial hypertrophy, as obtained
from isolated cardiomyocytes and/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 depict the temporal relationship among myocardial structural
and functional characteristics, the embryonic gene program, and transforming
growth factor (TGF)[beta]1 expression in euthyroid hereditary hypertrophic
cardiomyopathic hamsters (CMPH). This investigation was performed using
Western and Northern blot and in situ hybridization techniques. The results
show that in CMPH, the severity of the hemodynamic overload is not related
to any modification in structural myocardial characteristics (cardiac mass,
cardiomyocyte dimensions, total RNA, and protein content), whereas an early
activation of the embryonic gene program occurs in not yet overloaded 90-day-old
CMPH (left ventricular end diastolic pressure < 15 mm Hg). In these animals,
a 30% to 90% decrease in the [alpha] myosin heavy chain ([alpha]MHC) relative
content was found in ventricles, whereas [beta]MHC increased 5-fold. In
addition, the [alpha] skeletal actin expression was enhanced 2-fold versus
age-matched controls. No modifications were observed in myosin function
evaluated by in vitro motility assay, whereas the administration of L-thyroxine
(100 [mu]g/kg intraperitoneally daily) to CMPH was able to reinduce the
ventricular expression of the [alpha]MHC isoform (5-fold increase). Conversely,
no changes were found in [alpha] cardiac actin and myosin light chain 2
(MLC2) expression. A close temporal relationship occurred in CMPH ventricles
between the re-expression of the embryonic gene program and a 3-fold 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 echanical and hormonal stimuli, and that TGF[beta]1
is involved in regulating in vivo the ``embryonic step'' of myocardial hypertrophy.
Furthermore, the study offers new insights into the pathophysiologic mechanisms
leading to heart failure. |
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