Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

Junichi Omura, Kimio Satoh, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Masamichi Nogi, Tomohiro Otsuki, Katsuya Kozu, Kazuhiko Numano, Kota Suzuki, Shinichiro Sunamura, Shunsuke Tatebe, Tatsuo Aoki, Koichiro Sugimura, Satoshi Miyata, Yasushi Hoshikawa, Yoshinori Okada, Hiroaki Shimokawa

Research output: Contribution to journalArticle

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Abstract

Rationale: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective: To determine the role of endothelial AMPK in the development of PAH. Methods and Results: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK-/-), which were exposed to hypoxia. Under normoxic condition, eAMPK-/- mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPKflox/flox). In contrast, development of hypoxia-induced PH was accelerated in eAMPK-/- mice compared with controls. Furthermore, the exacerbation of PH in eAMPK-/- mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. Conclusions: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.

Original languageEnglish
Pages (from-to)197-209
Number of pages13
JournalCirculation Research
Volume119
Issue number2
DOIs
Publication statusPublished - 08-07-2016

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AMP-Activated Protein Kinases
Pulmonary Hypertension
Knockout Mice
Pulmonary Artery
Hypoxia
Smooth Muscle Myocytes
Blood Vessels
Cell Proliferation
Therapeutics
Metformin
Protein Kinase Inhibitors
Conditioned Culture Medium
Serum
Interferons
Intercellular Signaling Peptides and Proteins
Homeostasis
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Omura, Junichi ; Satoh, Kimio ; Kikuchi, Nobuhiro ; Satoh, Taijyu ; Kurosawa, Ryo ; Nogi, Masamichi ; Otsuki, Tomohiro ; Kozu, Katsuya ; Numano, Kazuhiko ; Suzuki, Kota ; Sunamura, Shinichiro ; Tatebe, Shunsuke ; Aoki, Tatsuo ; Sugimura, Koichiro ; Miyata, Satoshi ; Hoshikawa, Yasushi ; Okada, Yoshinori ; Shimokawa, Hiroaki. / Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice. In: Circulation Research. 2016 ; Vol. 119, No. 2. pp. 197-209.
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abstract = "Rationale: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective: To determine the role of endothelial AMPK in the development of PAH. Methods and Results: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK-/-), which were exposed to hypoxia. Under normoxic condition, eAMPK-/- mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPKflox/flox). In contrast, development of hypoxia-induced PH was accelerated in eAMPK-/- mice compared with controls. Furthermore, the exacerbation of PH in eAMPK-/- mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. Conclusions: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.",
author = "Junichi Omura and Kimio Satoh and Nobuhiro Kikuchi and Taijyu Satoh and Ryo Kurosawa and Masamichi Nogi and Tomohiro Otsuki and Katsuya Kozu and Kazuhiko Numano and Kota Suzuki and Shinichiro Sunamura and Shunsuke Tatebe and Tatsuo Aoki and Koichiro Sugimura and Satoshi Miyata and Yasushi Hoshikawa and Yoshinori Okada and Hiroaki Shimokawa",
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Omura, J, Satoh, K, Kikuchi, N, Satoh, T, Kurosawa, R, Nogi, M, Otsuki, T, Kozu, K, Numano, K, Suzuki, K, Sunamura, S, Tatebe, S, Aoki, T, Sugimura, K, Miyata, S, Hoshikawa, Y, Okada, Y & Shimokawa, H 2016, 'Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice', Circulation Research, vol. 119, no. 2, pp. 197-209. https://doi.org/10.1161/CIRCRESAHA.115.308178

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice. / Omura, Junichi; Satoh, Kimio; Kikuchi, Nobuhiro; Satoh, Taijyu; Kurosawa, Ryo; Nogi, Masamichi; Otsuki, Tomohiro; Kozu, Katsuya; Numano, Kazuhiko; Suzuki, Kota; Sunamura, Shinichiro; Tatebe, Shunsuke; Aoki, Tatsuo; Sugimura, Koichiro; Miyata, Satoshi; Hoshikawa, Yasushi; Okada, Yoshinori; Shimokawa, Hiroaki.

In: Circulation Research, Vol. 119, No. 2, 08.07.2016, p. 197-209.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

AU - Omura, Junichi

AU - Satoh, Kimio

AU - Kikuchi, Nobuhiro

AU - Satoh, Taijyu

AU - Kurosawa, Ryo

AU - Nogi, Masamichi

AU - Otsuki, Tomohiro

AU - Kozu, Katsuya

AU - Numano, Kazuhiko

AU - Suzuki, Kota

AU - Sunamura, Shinichiro

AU - Tatebe, Shunsuke

AU - Aoki, Tatsuo

AU - Sugimura, Koichiro

AU - Miyata, Satoshi

AU - Hoshikawa, Yasushi

AU - Okada, Yoshinori

AU - Shimokawa, Hiroaki

PY - 2016/7/8

Y1 - 2016/7/8

N2 - Rationale: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective: To determine the role of endothelial AMPK in the development of PAH. Methods and Results: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK-/-), which were exposed to hypoxia. Under normoxic condition, eAMPK-/- mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPKflox/flox). In contrast, development of hypoxia-induced PH was accelerated in eAMPK-/- mice compared with controls. Furthermore, the exacerbation of PH in eAMPK-/- mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. Conclusions: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.

AB - Rationale: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective: To determine the role of endothelial AMPK in the development of PAH. Methods and Results: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK-/-), which were exposed to hypoxia. Under normoxic condition, eAMPK-/- mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPKflox/flox). In contrast, development of hypoxia-induced PH was accelerated in eAMPK-/- mice compared with controls. Furthermore, the exacerbation of PH in eAMPK-/- mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. Conclusions: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.

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