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(Circulation Research. 2001;89:55.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Vascular Smooth Muscle Cell–Directed Overexpression of Heme Oxygenase-1 Elevates Blood Pressure Through Attenuation of Nitric Oxide–Induced Vasodilation in Mice

Tomihiko Imai, Toshisuke Morita, Takayuki Shindo, Ryozo Nagai, Yoshio Yazaki, Hiroki Kurihara, Makoto Suematsu, Shigehiro Katayama

From the Fourth Department of Internal Medicine (T.I., T.M., S.K.), Saitama Medical School, Saitama; Department of Cardiovascular Medicine (T.S.), Graduate School of Medicine, University of Tokyo; International Medical Center of Japan (Y.Y.), Tokyo; Division of Integrative Cell Biology, Department of Embryogenesis (H.K.), Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto; and Department of Biochemistry and Integrative Medical Biology (M.S.), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to Toshisuke Morita, MD, PhD, Fourth Department of Internal Medicine, Saitama Medical School, 38 Morohongo, Moroyama, Iruma-Gun, Saitama 350-0495, Japan. E-mail toshijpn{at}saitama-med.ac.jp

Abstract

Abstract—To elucidate pathophysiological roles of heme oxygenase (HO)-1 in regulation of vascular tone in vivo, we have developed and characterized transgenic (Tg) mice that overexpress HO-1 site specifically in vascular smooth muscle cells (VSMCs). The Tg mice were generated by use of human HO-1 cDNA under the control of SM22- promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice exhibited a significant increase in arterial pressure at various ages and displayed impaired nitrovasodilatory responses in isolated aortic segments versus nontransgenic littermates while enhancing their nitric oxide (NO) production. The pressure of Tg mice was unchanged by systemic administration of either N-nitro-L-arginine or SNP. Furthermore, the isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin IX, an HO inhibitor. On the other hand, 3-(5'-hydroxymethyl-2' furyl)-1-benzyl-indazol (YC-1), an NO-independent activator of sGC, increased cGMP and relaxed aortas from Tg mice to levels comparable with those from nontransgenic mice, which indicates that contents of functionally intact sGC are unlikely to differ between the two systems. These findings suggest that site-specific overexpression of HO-1 in VSMCs suppresses vasodilatory response to NO and thereby leads to an elevation of arterial pressure.

Key Words: heme oxygenase-1 • transgenic mice • carbon monoxide • soluble guanylate cyclase • hypertension

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