Chronic injuries to the mammalian myocardium induce maladaptive changes which are initiated at the transcriptional level of myocardial gene expression. However, the regulatory mechanisms responsible for these changes are still unknown. We have uncovered one of such mechanisms while studying the function of a protein called MyotrophinA/1 (MyoA/1), whose levels were found to be elevated in the normal neonatal myocardium and in failing adult mammalian hearts. The PI has recently demonstrated that Myo/V1 is an intracellular cytosolic protein and functions as a zipper chaperone capable of generating active NFkB dimers. Consistent with this earlier finding, our recent preliminary studies show that the chaperone function of MyoA/1 on NFkappaB is mediated through a reversible thiol/disulphide exchange mechanism operating under the control of the redox environment of the cell. Furthermore, in the early neonatal rat myocardium we have observed a transient change in intracellular redox state followed by transient upregulation of Myo/V1 and de novo activation of NFkappaB dimers. A strong temporal correlation among these processes suggested that this de novo activation of NFkappaB rheostat is Myo/V1 mediated and regulated by the cellular redox state. Our bioinformatic studies on isogene promoters and preliminary experimental results further indicate that this NFkappaB rheostat is responsible for the transition from fetal to adult pattern of isogene expression. To prove this hypothesis, we have envisioned four specific aims:
The specific aim 1 will delineate the molecular steps in the mechanism of redox activation of NFkappaB by Myo/V1 using in vitro biochemical experiments.
The specific aims 2 and 3 will define that the 'de novo activated NFkappaB rheostat' in neonatal myocardium is under the control of cellular redox state, MyoA/1 and it targets isogene promoters to initiate the switch from fetal to adult isogene expression.
The specific aim 4 will define that Myo/V1 is essential for the redox activation of NFkappaB rheostat and for the switch in LDH isozyme genes' expression. Given that many myocardial diseases are accompanied by the activation of NFkappaB dimers and fetal gene re-expression, these studies are relevant and may one day translate into new therapies designed to protect the heart against chronic injury.
| Knuefermann, Pascal; Shi, Shu-Ping; Chen, Peter et al. (2006) Myotrophin/V-1 does not act as an extracellular signal to induce myocyte hypertrophy. Tex Heart Inst J 33:281-9 |
