Abstract 16197: Nucleostemin Induces Cardiac Myocyte Hypertrophy via Transcription Factor c-Myc
Nucleostemin (NS) is a nucleolar GTP binding, stress sensor protein with pro-proliferative and pro-survival properties that is highly enriched in mitotic cells. NS expression increases upon pathological challenge in the heart, such as pressure overload and myocardial infarction, while being expressed at low levels in the adult heart. Based on the rationale that NS upregulation in the injured myocardium correlates with, and could contribute to, increased cardiac remodeling, hypertrophic growth and repair processes, we hypothesize that NS is an inducer of cardiac myocyte (CM) hypertrophy. Phenotypic markers of cardiac hypertrophy are increased in cultured neonatal rat CMs over-expressing NS (Ad-NS), as indicated by increases in myocyte cross sectional area (1.6 fold, p<0.01), mRNA levels of fetal cardiac genes like atrial (ANP, 6.5 fold) and brain natriuretic peptide (BNP, 2 fold) and myosin heavy chain protein (2.2 fold). Knockdown of NS by short hairpin RNA inhibits hypertrophy as indicated by reduced cell size at baseline (-14.7%, p<0.01) and upon treatment with phenylephrine (PE), an inducer of cardiac hypertrophy (-22.4% vs PE treated control cells, p<0.01). NS over-expression also increases protein levels of c-Myc (18.3 fold, p<0.01), a pro-proliferative transcription factor which is both necessary and sufficient for regulation of NS. Correlation between NS and c-Myc expression and a previously established role of c-Myc as a regulator of CM hypertrophy suggests that NS-induced hypertrophy is c-Myc dependent. Silencing c-Myc attenuates NS- induced cardiac hypertrophy in vitro, as indicated by decreased CM size (-21.2% vs Ad-NS, p<0.05), ANP mRNA (-89.5% vs Ad-NS, p<0.05) and myosin heavy chain protein expression (-29.6% vs Ad-NS). Consistent with findings in vitro, cardiac specific over-expression of NS in transgenic mice hearts shows increased cell size (1.71 fold vs Non-transgenic mice, p<0.01), accompanied by increased c-Myc expression, suggestive of increased hypertrophy. These findings which indicate that NS plays a role in myocyte hypertrophy, a previously unrecognized function for this protein, are of significant interest because it identifies nucleolar proteins as novel regulators of hypertrophic signaling and remodeling.
- © 2012 by American Heart Association, Inc.