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Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart

Peter Razeghi^*, Malgorzata Buksinska-Lisik^*, Nanthini Palanichamy, Stanislaw Stepkowski, O. Howard Frazier and Heinrich Taegtmeyer^*,,1

^* Division of Cardiology and

Division of Organ Transplantation, University of Texas Houston-Medical School, Houston, Texas, USA; and

Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas, USA

¹Correspondence: Department of Internal Medicine, Division of Cardiology, University of Texas Houston-Medical School, 6431 Fannin, MSB 1.222, Houston, TX 77030, USA. E-mail: heinrich.taegtmeyer{at}uth.tmc.edu

Mechanical unloading of the rat heart increases both protein synthesis and protein degradation. The transcriptional mechanism underlying increased protein synthesis during atrophic remodeling is not known. The aim of this study was to identify transcriptional regulators and the gene expression profile regulating protein synthesis in the unloaded rat heart and in the unloaded failing human heart. We measured DNA binding activity, transcript levels, and protein expression of transcriptional regulators of protein synthesis in a model of atrophic remodeling induced by heterotopic transplantation of the rat heart (duration 1 and 7 days). Using microarray analysis and quantitative RT-polymerase chain reaction, we found an increase in c-myc-regulated gene expression including an induction of ribosomal subunit messenger RNA’s (RPS 10, RPL 21) and rRNA (18S). Consistent with the gene expression profile, DNA binding activity of c-myc and the nuclear protein concentration of its coactivator, upstream binding factor (UBF), increased in the atrophied heart whereas protein levels of the c-myc inhibitor MAD1 decreased. We found the same increase of ribosomal subunit messenger RNA and rRNA in 21 paired samples of failing human hearts obtained before and after left ventricular assist device treatment (mean duration: 157±31 days). In summary, mechanical unloading increases c-myc activity and c-myc-regulated gene expression in the rat heart. Changes in transcript levels of genes regulating ribosomal biogenesis in the unloaded rat heart resemble those found in the unloaded failing human heart. We concluded c-myc and c-myc-regulated gene expression are transcriptional regulators of protein synthesis during atrophic remodeling of the heart.—Razeghi, P., Buksinska-Lisik, M., Palanichamy, N., Stepkowski, S., Frazier, O. H., Taegtmeyer, H. Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart.

Key Words: failing human heart • LVAD • reverse remodeling • c-myc

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				P. RAZEGHI and H. TAEGTMEYER Hypertrophy and Atrophy of the Heart: The Other Side of Remodeling Ann. N.Y. Acad. Sci., October 1, 2006; 1080(1): 110 - 119. [Abstract] [Full Text] [PDF]