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Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters
P Di Nardo1, R Fiaccavento, A Natali
1Dipartimento di Medicina Interna, Università di Roma Tor Vergata, Italy.
Insights
This study reveals that in cardiomyopathic hamsters, an early embryonic gene program activation precedes structural changes in myocardial hypertrophy. Transforming growth factor beta 1 (TGF-β1) is implicated in regulating this "embryonic step" of heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pathophysiology of Heart Disease
Background:
- Current models of myocardial hypertrophy lack in vivo hierarchical understanding.
- Isolated cardiomyocyte and animal models with aortic banding have limitations.
Purpose of the Study:
- To elucidate the temporal relationship between myocardial changes, embryonic gene program activation, and TGF-β1 expression.
- To investigate these mechanisms in hereditary hypertrophic cardiomyopathic hamsters (CMPH) in vivo.
Main Methods:
- Western blot
- Northern blot
- In situ hybridization
- In vitro motility assay
Main Results:
- Early embryonic gene program activation in CMPH occurs independently of hemodynamic overload.
- Significant alterations in myosin heavy chain (MHC) isoforms (decreased alpha-MHC, increased beta-MHC) and enhanced alpha-skeletal actin expression were observed.
- Transforming growth factor beta 1 (TGF-β1) expression increased concurrently with embryonic gene re-expression.
Conclusions:
- CMPH model is valuable for studying embryonic gene expression in hypertrophic ventricles without mechanical/hormonal stimuli.
- TGF-β1 plays a role in regulating the embryonic gene program during myocardial hypertrophy in vivo.
- Findings offer new insights into heart failure pathophysiology.
Abstract:
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 micrograms/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 mechanical 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.