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Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung

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Abstract

The present study aimed to investigate the effects of olmesartan, an antagonist for angiotensin II receptor type 1(AT1), on the activation of extracellular signal-regulated kinases (ERK)1/2, tissue remodeling, and pro-inflammatory signals in the right ventricle and lung of mice during the early phase of hypobaric hypoxia. Phosphorylation of ERK1/2 in both tissue types in response to hypoxia peaked at 1–3 days, and declined rapidly in the right ventricle, whereas in the lung it was sustained for at least 8 days. Upregulation of angiotensinogen mRNA was observed in the hypoxic lung at 4–9 days, but not in the hypoxic right ventricle and pulmonary artery. Olmesartan inhibited the hypoxia-induced phosphorylation of ERK1/2 in the lung, but not in the right ventricle. Neither right ventricular hypertrophy nor the thickening of the intrapulmonary arterial wall was ameliorated by olmesartan. However, this drug inhibited the expression of the mRNA for angiotensinogen and several pro-inflammatory factors, including interleukin-6 and inducible nitric oxide synthase in the hypoxic lung. These results suggest that olmesartan blocks a potential positive feedback loop of the angiotensin II-AT1 receptor system, which may lead to attenuate pro-inflammatory signals in the mouse lung, that are associated with hypoxic pulmonary hypertension, without inducing any appreciable effects on the compensatory cardiopulmonary hypertrophy at an early phase of exposure to a hypobaric hypoxic environment.

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Abbreviations

ACE:

angiotensin-converting enzyme

Ang:

angiotensinogen

Ang II:

angiotensin II

AT1 and AT2:

Ang II receptor types 1 and 2

CMC:

carboxymethylcellulose

COX:

cyclooxygenase

ERK:

extracellular signal-regulated protein kinase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

HO-1:

heme oxygenase-1

IL-6:

interleukin 6

iNOS:

inducible nitric oxide synthase

KC:

keratinocyte-derived chemokines

MAPK:

mitogen-activated protein kinase

MCP:

monocyte chemoattractant protein

MEK:

MAPK/ERK kinase

MIP:

macrophage inflammatory protein

PDGFR:

platelet-derived growth factor receptor

RT-PCR:

reverse-transcription and polymerase chain reaction

TNF-α:

tumor necrosis factor-α

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Acknowledgments

We would like to thank Sankyo, for providing us with the olmesartan. We are also grateful to Mr. Y. Okamoto, Ms. K. Sato, and Mr. T. Kitayama for their technical assistance with the animal handling. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (14572059) from the Ministry of Education, Science, Sports, and Culture of Japan from 2002–2004.

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  1. Department of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi, Shizuoka, 422-8526, Japan

    Yoshiyuki Tanabe, Yuki Morikawa, Takao Kato, Satoshi Kanai, Taichi Watakabe, Ami Nishijima & Koichi Nakayama

  2. Biosafety Research Center, Foods, Drugs and Pesticides, 582-2 Arahama, Shioshinden, Fukude, Iwata-shi, Shizuoka, 437-1312, Japan

    Hijiri Iwata, Kaori Isobe & Mayumi Ishizaki

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  1. Yoshiyuki Tanabe
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  2. Yuki Morikawa
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Correspondence to Koichi Nakayama.

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Tanabe, Y., Morikawa, Y., Kato, T. et al. Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung. Naunyn-Schmied Arch Pharmacol 374, 235–248 (2006). https://doi.org/10.1007/s00210-006-0110-1

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