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(Hypertension. 1997;29:381.)
© 1997 American Heart Association, Inc.

State-of-the-Art-Lecture

Opposite Regulation of Gax Homeobox Expression by Angiotensin II and C-Type Natriuretic Peptide

Jun Yamashita; Hiroshi Itoh; Yoshihiro Ogawa; Naohisa Tamura; Kazuhiko Takaya; Toshio Igaki; Kentaro Doi; Tae-Hwa Chun; Mayumi Inoue; Ken Masatsugu; Kazuwa Nakao

From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.

Correspondence to Hiroshi Itoh, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp

Growth arrest-specific homeobox (Gax) gene was isolated from rat aorta cDNA library and its expression was largely confined to the cardiovascular tissues. Gax gene was rapidly downregulated by platelet-derived growth factor in vascular smooth muscle cells (VSMCs) and overexpressed Gax was reported to reduce the neointimal thickening after balloon injury in vivo. We have demonstrated that angiotensin II (Ang II) stimulates vascular growth. In contrast, we also reported that C-type natriuretic peptide (CNP) is secreted from vascular endothelial cells to act as a novel endothelium-derived relaxing peptide and inhibits vascular growth via cGMP cascade. In the present study, we examined the effects of Ang II and CNP on Gax gene expression in VSMCs. In quiescent rat aortic VSMCs, Gax mRNA (2.3 kb) level became negligible 6 hours after the addition of Ang II (10^-6 mol/L). The inhibitory action of Ang II on Gax mRNA expression (ED₅₀: 10^-11 mol/L) was almost completely blocked by an AT₁R antagonist, CV11974. In contrast, CNP 10^-6 mol/L augmented Gax mRNA expression to exhibit 1.8-fold increase of the control 12 hours after the stimulation. This effect of CNP was mimicked by the addition of 8-bromoadenosine 3':5'-cyclic monophosphate. The addition of C-ANF[4–23], an atrial natriuretic peptide-C receptor-specific agonist and devoid of stimulating cGMP production, exhibited no effect on Gax mRNA expression. Simultaneous administration of Ang II and CNP revealed that CNP (10^-6 mol/L) significantly attenuated the inhibitory 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 regulates the cell cycle and/or phenotype of VSMCs for vascular remodeling in hypertension and atherosclerosis.

Key Words: natriuretic peptides • angiotensin II • growth arrest-specific homeobox • homeobox • growth • gene regulation • vascular smooth muscle cells

Abbreviations: 8-Br-cGMP = 8-bromoadenosine-cGMP • Ang II = angiotensin II • ANP = atrial natriuretic peptide • CNP = C-type natriuretic peptide • DSF = defined serum-free • Gax = growth arrest-specific homeobox gene • MAPK = mitogen-activated protein kinase • NPS = natriuretic peptide system • PCR = polymerase chain reaction • PDGF = platelet-derived growth factor • RAS = renin-angiotensin system • VSMC = vascular smooth muscle cell

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