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

研究成果: Article

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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-α 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 Nω-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.

元の言語English
ページ(範囲)55-62
ページ数8
ジャーナルCirculation research
89
発行部数1
DOI
出版物ステータスPublished - 2001 7 6

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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