Published Online
on February 9, 2004

A more recent version of this article appeared on March 9, 2004

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Submitted on March 5, 2003
Revised on October 17, 2003
Accepted on October 20, 2003

Endogenous Adrenomedullin Protects Against Vascular Response to Injury in Mice

Junsuke Kawai MD, Katsuyuki Ando MD, Akihiro Tojo MD, Tatsuo Shimosawa MD, Katsutoshi Takahashi MD, Maristela Lika Onozato MD, Masao Yamasaki MD, Teruhiko Ogita MD, Takashi Nakaoka MD, and Toshiro Fujita MD^*

From the Department of Internal Medicine, School of Medicine, University of Tokyo, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.

Background--In our previous study, adrenomedullin (AM) overexpression could limit the arterial intimal hyperplasia induced by cuff injury in rats. However, it remains to be elucidated whether endogenous AM plays a role against vascular injury.

Methods and Results--We used the AM knockout mice to investigate the effect of endogenous AM. Compared with wild-type (AM^+/+) mice, heterozygous AM knockout (AM^+/-) mice had the increased intimal thickening of the cuff-injured femoral artery, concomitantly with lesser AM staining. In AM^+/- mice, cuff placement increased both the production of superoxide anions (O₂^-) measured by coelentarazine chemiluminescence and the immunostaining of p67^phox and gp91^phox, subunits of NAD(P)H oxidase in the adventitia, associated with the increment of CD45-positive leukocytes, suggesting that the stimulated formation of radical oxygen species accompanied chronic adventitial inflammation. Not only the AM gene transfection but also the treatment of NAD(P)H oxidase inhibitor apocynin and membrane-permeable superoxide dismutase mimetic tempol could limit cuff-induced intimal hyperplasia in AM^+/- mice, associated with the inhibition of O₂^- formation in cuff-injured artery.

Conclusions--The overproduction of oxidative stress induced by the increased NAD(P)H oxidase activity might be involved in cuff-injured arterial intimal hyperplasia in AM^+/- mice. Thus, it is suggested that endogenous AM possesses a protective action against the vascular response to injury, possibly through the inhibition of oxidative stress production.

Key words: antioxidant • inflammation • endothelium • arteries • peptides

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