OPPOSITE REGULATION OF GAX HOMEOBOX EXPRESSION BY ANGIOTENSIN-II AND C-TYPE NATRIURETIC PEPTIDE

Growth arrest-specific homeobox (Gax) gene was isolated from rat aorta cDNA library and its expression was largely confined to the cardiovas cular tissues. Gax gene was rapidly downregulated by platelet-derived growth factor in vascular smooth muscle cells (VSMCs) and overexpresse d Gax was re ported to reduce the neointimal thickening after balloon injury in vivo. We have demonstrated that angiotensin II (Ang II) stim ulates vascular growth. In contrast, we also reported that C-type natr iuretic peptide (CNP) is secreted from vascular endothelial cells to a ct as a novel endothelium-derived relaxing peptide and inhibits vascul ar growth via cGMP cascade. In the present study, we examined the effe cts of Ang II and CNP on Gax gene expression in VSMCs. In quiescent ra t aortic VSMCs, Gax mRNA (2.3 kb) level became negligible 6 hours afte r the addition of Ang II (10(-6) mol/L). The inhibitory action of Ang II on Gax mRNA expression (EDS,: 10(-11) mol/L) was almost completely blocked by an AT(1)R antagonist, CV11974. In contrast, CNP 10(-6) mol/ L augmented Gax mRNA expression to exhibit 1.8-fold increase of the co ntrol 12 hours after the stimulation. This effect of CNP was mimicked by the addition of 8-bromoadenosine 3':5'-cyclic monophosphate. The ad dition of C-ANF[4-23], an atrial natriuretic peptide-C receptor-specif ic agonist and devoid of stimulating cGMP production, exhibited no eff ect on Gax mRNA expression. Simultaneous administration of Ang II and CNP revealed that CNP (10(-6) mol/L) significantly attenuated the inhi bitory action of Ang II (10(-10) mol/L) on Gax mRNA expression. These results suggest that Gax is a common transcription factor involved in the signaling pathway of vascular growth for Ang II and CNP and regula tes the cell cycle and/or phenotype of VSMCs for vascular remodeling i n hypertension and atherosclerosis.