Selenoprotein P promotes the development of pulmonary arterial hypertension: Possible novel therapeutic target

Nobuhiro Kikuchi, Kimio Satoh, Ryo Kurosawa, Nobuhiro Yaoita, Md Elias-Al-Mamun, Mohammad Abdul Hai Siddique, Junichi Omura, Taijyu Satoh, Masamichi Nogi, Shinichiro Sunamura, Satoshi Miyata, Yoshiro Saito, Yasushi Hoshikawa, Yoshinori Okada, Hiroaki Shimokawa

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. METHODS: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 lowmolecular- weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. RESULTS: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice (SeP-/-) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxiainduced PH. Furthermore, PASMC-specific SeP-/- mice showed reduced hypoxiainduced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1a and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. CONCLUSIONS: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.

Original languageEnglish
Pages (from-to)600-623
Number of pages24
JournalCirculation
Volume138
Issue number6
DOIs
Publication statusPublished - 01-01-2018

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Selenoprotein P
Pulmonary Hypertension
Pulmonary Artery
Smooth Muscle Myocytes
Therapeutics
Microarray Analysis
Knockout Mice
Biomarkers
Serum
Apoptosis
Right Ventricular Hypertrophy

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kikuchi, N., Satoh, K., Kurosawa, R., Yaoita, N., Elias-Al-Mamun, M., Siddique, M. A. H., ... Shimokawa, H. (2018). Selenoprotein P promotes the development of pulmonary arterial hypertension: Possible novel therapeutic target. Circulation, 138(6), 600-623. https://doi.org/10.1161/CIRCULATIONAHA.117.033113
Kikuchi, Nobuhiro ; Satoh, Kimio ; Kurosawa, Ryo ; Yaoita, Nobuhiro ; Elias-Al-Mamun, Md ; Siddique, Mohammad Abdul Hai ; Omura, Junichi ; Satoh, Taijyu ; Nogi, Masamichi ; Sunamura, Shinichiro ; Miyata, Satoshi ; Saito, Yoshiro ; Hoshikawa, Yasushi ; Okada, Yoshinori ; Shimokawa, Hiroaki. / Selenoprotein P promotes the development of pulmonary arterial hypertension : Possible novel therapeutic target. In: Circulation. 2018 ; Vol. 138, No. 6. pp. 600-623.
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abstract = "BACKGROUND: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. METHODS: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 lowmolecular- weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. RESULTS: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice (SeP-/-) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxiainduced PH. Furthermore, PASMC-specific SeP-/- mice showed reduced hypoxiainduced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1a and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. CONCLUSIONS: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.",
author = "Nobuhiro Kikuchi and Kimio Satoh and Ryo Kurosawa and Nobuhiro Yaoita and Md Elias-Al-Mamun and Siddique, {Mohammad Abdul Hai} and Junichi Omura and Taijyu Satoh and Masamichi Nogi and Shinichiro Sunamura and Satoshi Miyata and Yoshiro Saito and Yasushi Hoshikawa and Yoshinori Okada and Hiroaki Shimokawa",
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Kikuchi, N, Satoh, K, Kurosawa, R, Yaoita, N, Elias-Al-Mamun, M, Siddique, MAH, Omura, J, Satoh, T, Nogi, M, Sunamura, S, Miyata, S, Saito, Y, Hoshikawa, Y, Okada, Y & Shimokawa, H 2018, 'Selenoprotein P promotes the development of pulmonary arterial hypertension: Possible novel therapeutic target', Circulation, vol. 138, no. 6, pp. 600-623. https://doi.org/10.1161/CIRCULATIONAHA.117.033113

Selenoprotein P promotes the development of pulmonary arterial hypertension : Possible novel therapeutic target. / Kikuchi, Nobuhiro; Satoh, Kimio; Kurosawa, Ryo; Yaoita, Nobuhiro; Elias-Al-Mamun, Md; Siddique, Mohammad Abdul Hai; Omura, Junichi; Satoh, Taijyu; Nogi, Masamichi; Sunamura, Shinichiro; Miyata, Satoshi; Saito, Yoshiro; Hoshikawa, Yasushi; Okada, Yoshinori; Shimokawa, Hiroaki.

In: Circulation, Vol. 138, No. 6, 01.01.2018, p. 600-623.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selenoprotein P promotes the development of pulmonary arterial hypertension

T2 - Possible novel therapeutic target

AU - Kikuchi, Nobuhiro

AU - Satoh, Kimio

AU - Kurosawa, Ryo

AU - Yaoita, Nobuhiro

AU - Elias-Al-Mamun, Md

AU - Siddique, Mohammad Abdul Hai

AU - Omura, Junichi

AU - Satoh, Taijyu

AU - Nogi, Masamichi

AU - Sunamura, Shinichiro

AU - Miyata, Satoshi

AU - Saito, Yoshiro

AU - Hoshikawa, Yasushi

AU - Okada, Yoshinori

AU - Shimokawa, Hiroaki

PY - 2018/1/1

Y1 - 2018/1/1

N2 - BACKGROUND: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. METHODS: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 lowmolecular- weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. RESULTS: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice (SeP-/-) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxiainduced PH. Furthermore, PASMC-specific SeP-/- mice showed reduced hypoxiainduced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1a and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. CONCLUSIONS: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.

AB - BACKGROUND: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. METHODS: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 lowmolecular- weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. RESULTS: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice (SeP-/-) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxiainduced PH. Furthermore, PASMC-specific SeP-/- mice showed reduced hypoxiainduced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1a and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. CONCLUSIONS: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.

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