Angiotensin II-induced Hypertrophy of Rat Vascular Smooth Muscle Is Associated with Increased 18 S rRNA Synthesis and Phosphorylation of the rRNA Transcription Factor, Upstream Binding Factor

James C Hershey,Martina Hautmann,Maria M Thompson,Lawrence I Rothblum,Timothy A.J Haystead,Gary K Owens

doi:10.1074/jbc.270.42.25096

Abstract

Hypertrophy of vascular smooth muscle cells (VSMC) is an important adaptive response of hypertension. Drug intervention studies have implicated a role for angiotensin II (A-II) in the mediation of VSMC hypertrophy in vivo, and A-II is a potent hypertrophic agent for VSMC in culture. Our laboratory has previously shown that A-II-induced hypertrophy of cultured VSMC is due in part to generalized increases in protein synthesis and increased content of rRNA. The aim of the present study was to determine if A-II stimulates rRNA gene synthesis and whether the rRNA transcription factor, upstream binding factor (UBF), is involved. Nuclear run-on analysis demonstrated that A-II induced a greater than 5-fold increase in rRNA gene synthesis within 6 h of stimulation. A-II also stimulated a rapid increase in UBF phosphorylation as well as nucleolar localization, but no changes in the content of UBF. Phosphoamino acid analysis showed that phosphorylation occurred only on serine residue(s). Results demonstrate that increased transcription of ribosomal DNA contributes to the A-II-induced increase in protein synthesis and VSMC hypertrophy, and suggest that an important regulatory event in this pathway may be the phosphorylation and/or nucleolar localization of UBF.

Highlights

Hypertrophy of vascular smooth muscle cells (VSMC) is an important adaptive response of hypertension
We demonstrate that stimulation of cultured VSMC with angiotensin II (A-II) resulted in increased rRNA synthesis and a notable increase in phosphorylation and nucleolar localization of upstream binding factor (UBF)
A-II-induced hypertrophy of vascular smooth muscle cells in culture has been shown to be associated with a generalized increase in protein synthesis as well as selective increases in synthesis of cell-specific proteins such as SM ␣-actin and SM myosin heavy chain [23, 24]

Summary

Introduction

Hypertrophy of vascular smooth muscle cells (VSMC) is an important adaptive response of hypertension. The arterial medial thickening is believed to represent an important adaptive response to normalize the elevated wall stress that occurs secondary to the increased blood pressure [3] Previous studies in this and other laboratories have demonstrated that medial thickening, at least in large conduit vessels, is due in part to increased vascular smooth muscle cell (VSMC) content or mass, which. Consistent with in vivo studies, several laboratories, including our own, have shown that A-II stimulates increased protein synthesis and cellular hypertrophy in cultured VSMC via stimulation of angiotensin AT1 receptors [12, 13]. The mechanism of this effect is not clear. The A-II-induced hypertrophy of VSMC appears to be direct [12, 18]

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Conclusion