Increased expression of UBF is a critical determinant for rRNA synthesis and hypertrophic growth of cardiac myocytes

Recent evidence suggests that increased translational efficiency of existin g ribosomes alone is insufficient to account for the hypertrophic growth of cardiomyocytes and that synthesis of new functional ribosomes must occur. The rate-limiting step in ribosome accumulation is the transcription of the ribosomal 45S genes (rDNA) by RNA polymerase I. Our previous studies have demonstrated that increases in the expression of the rDNA transcription fac tor UBF correlated with hypertrophy of neonatal cardiomyocytes. These studi es expand this observation to examine directly the hypothesis that increase d UBF levels are an essential requirement for the initiation of cardiac hyp ertrophy. We demonstrate that the introduction of UBF antisense RNA into my ocytes, using adenovirus approaches, efficiently inhibits UBF accumulation during induction of cardiomyocyte hypertrophy. Moreover, this approach resu lts in a significant reduction in rDNA transcription, rRNA levels, and prot ein accumulation, which are all the hallmarks of cardiac growth. Furthermor e, UBF antisense RNA expression did not alter reexpression of the fetal gen e program, which confirmed that the effect was specific for transcription b y RNA polymerase I. These findings demonstrate that an increase in rRNA syn thesis is required for hypertrophy of cardiomyocytes and also implicate UBF as a major regulatory factor in this process. Approaches that target UBF a ctivity may be of therapeutic use in the regression of pathophysiological c ardiac hypertrophy.