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(Circulation. 2004;109:2246-2251.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia

Hiromitsu Matsui, MD; Tatsuo Shimosawa, MD, PhD; Kanami Itakura, MD; Xing Guanqun, MD; Katsuyuki Ando, MD, PhD; Toshiro Fujita, MD, PhD

From the Department of Nephrology and Endocrinology, Faculty of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Correspondence to Toshiro Fujita, MD, Department of Nephrology and Endocrinology, Faculty of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku Tokyo, 113-8655, Japan. E-mail fujita-dis{at}h.u-tokyo.ac.jp

Received May 30, 2003; de novo received November 13, 2003; revision received January 27, 2004; accepted February 4, 2004.

Background— Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM^+/–) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia.

Methods and Results— Ten-week-old male wild-type (AM^+/+) or AM^+/– mice were housed under 10% oxygen conditions for 3 to 21 days. In AM^+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM^+/– mice housed under hypoxia than in AM^+/+ mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM^+/– mice than in AM^+/+ mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM^+/+ but also AM^+/– mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung.

Conclusions— The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.

Key Words: mice, knockout • remodeling • stress, oxidative • hypertension, pulmonary

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