Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia

Hisashi Nagai, Ichiro Kuwahira, Daryl O. Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Sayoko Ogura, Takashi Sonobe, Tadakatsu Inagaki, Yutaka Fujii, Rutsuko Yamaguchi, Lisa Wingenfeld, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, Koichi Uemura, James T. Pearson, Mikiyasu Shirai

Research output: Contribution to journalArticle

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Abstract

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β<inf>1</inf> - adrenergic receptors (AR) (brain) and peripheral β<inf>2</inf> AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β<inf>3</inf> AR. However, the relationship between IH and β<inf>3</inf> AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β<inf>3</inf> AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β<inf>3</inf> AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O<inf>2</inf>) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of proinflammatory pulmonary macrophages. In these macrophages, both β<inf>3</inf> AR and iNOS were upregulated and stimulation of the β<inf>3</inf> AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β<inf>3</inf> AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β<inf>3</inf> AR/iNOS signaling in chronic IH.

Original languageEnglish
Article numbere0131923
JournalPLoS One
Volume10
Issue number7
DOIs
Publication statusPublished - 2015 Jul 1
Externally publishedYes

Fingerprint

vasoconstriction
Alveolar Macrophages
adrenergic receptors
Nitric Oxide Synthase Type II
Vasoconstriction
Adrenergic Receptors
Rats
hypoxia
macrophages
lungs
Lung
rats
Macrophages
Chemical activation
Up-Regulation
monocytes
Hypoxia
inducible nitric oxide synthase
Synchrotrons
secretion

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. / Nagai, Hisashi; Kuwahira, Ichiro; Schwenke, Daryl O.; Tsuchimochi, Hirotsugu; Nara, Akina; Ogura, Sayoko; Sonobe, Takashi; Inagaki, Tadakatsu; Fujii, Yutaka; Yamaguchi, Rutsuko; Wingenfeld, Lisa; Umetani, Keiji; Shimosawa, Tatsuo; Yoshida, Kenichi; Uemura, Koichi; Pearson, James T.; Shirai, Mikiyasu.

In: PLoS One, Vol. 10, No. 7, e0131923, 01.07.2015.

Research output: Contribution to journalArticle

Nagai, H, Kuwahira, I, Schwenke, DO, Tsuchimochi, H, Nara, A, Ogura, S, Sonobe, T, Inagaki, T, Fujii, Y, Yamaguchi, R, Wingenfeld, L, Umetani, K, Shimosawa, T, Yoshida, K, Uemura, K, Pearson, JT & Shirai, M 2015, 'Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia', PLoS One, vol. 10, no. 7, e0131923. https://doi.org/10.1371/journal.pone.0131923
Nagai, Hisashi ; Kuwahira, Ichiro ; Schwenke, Daryl O. ; Tsuchimochi, Hirotsugu ; Nara, Akina ; Ogura, Sayoko ; Sonobe, Takashi ; Inagaki, Tadakatsu ; Fujii, Yutaka ; Yamaguchi, Rutsuko ; Wingenfeld, Lisa ; Umetani, Keiji ; Shimosawa, Tatsuo ; Yoshida, Kenichi ; Uemura, Koichi ; Pearson, James T. ; Shirai, Mikiyasu. / Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β<inf>3</inf> AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. In: PLoS One. 2015 ; Vol. 10, No. 7.
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abstract = "Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1 - adrenergic receptors (AR) (brain) and peripheral β2 AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3 AR. However, the relationship between IH and β3 AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3 AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3 AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21{\%} O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of proinflammatory pulmonary macrophages. In these macrophages, both β3 AR and iNOS were upregulated and stimulation of the β3 AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3 AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3 AR/iNOS signaling in chronic IH.",
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AU - Sonobe, Takashi

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AU - Fujii, Yutaka

AU - Yamaguchi, Rutsuko

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