Key result
Transcription of RFC40 is suppressed in normal adult cardiac myocytes, and its insufficient re-expression during right ventricular hypertrophy or experimental knock-down causes chromosomal missegregation and aneuploidy.
Insufficient re-expression of RFC40 in adult cardiac myocytes during right ventricular hypertrophy may be responsible for chromosomal missegregation and aneuploidy.
No immediate clinical implications; hypothesis-generating for RFC40 in cardiac aneuploidy, requires human validation.
BACKGROUND: Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) and DNA polymerase δ (Pol δ) proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied. METHODS: We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol δ message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control) and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH) for rat chromosome 12. RESULTS: RFC40-mRNA and protein was undetectable, whereas Pol δ message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol δ message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re-expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers. CONCLUSION: Our novel findings suggest that transcription of RFC40 is suppressed in the normal adult cardiac myocytes and its insufficient re-expression may be responsible for causing chromosomal missegregation/aneuploidy and in cardiac myocytes during right ventricular hypertrophy.
No takes yet. Share an insight, caveat, or question.
Ata et al. (2012) studied Right ventricular hypertrophy. RFC40 knock-down / Sugen-5416-induced PAH vs. Control / Non-targeting siRNA was evaluated on Chromosomal missegregation and aneuploidy. Transcription of RFC40 is suppressed in normal adult cardiac myocytes, and its insufficient re-expression during right ventricular hypertrophy or experimental knock-down causes chromosomal missegregation and aneuploidy.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: