ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure: A Possible Novel Therapeutic Target

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

Research output: Contribution to journalArticle

Abstract

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. OBJECTIVE: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. METHODS AND RESULTS: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTSΔSM22). Hypoxia-induced PH was attenuated in ADAMTSΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8ΔαMHC). ADAMTS8ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. CONCLUSIONS: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

Original languageEnglish
Pages (from-to)884-906
Number of pages23
JournalCirculation research
Volume125
Issue number10
DOIs
Publication statusPublished - 25-10-2019

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Pulmonary Hypertension
Smooth Muscle Myocytes
Pulmonary Artery
Therapeutics
Cell Proliferation
AMP-Activated Protein Kinases
Knockout Mice
Lung
Mebendazole
Dynamins
Thrombospondins
Disintegrins
Right Ventricular Function
Parasitic Diseases
Metalloproteases
Microarray Analysis
Matrix Metalloproteinases
Vascular Smooth Muscle
Cardiac Myocytes
Extracellular Matrix

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 ; Ohtsuki, Tomohiro ; Al-Mamun, Md Elias ; Siddique, Mohammad Abdul Hai ; Yaoita, Nobuhiro ; Sunamura, Shinichiro ; Miyata, Satoshi ; Hoshikawa, Yasushi ; Okada, Yoshinori ; Shimokawa, Hiroaki. / ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure : A Possible Novel Therapeutic Target. In: Circulation research. 2019 ; Vol. 125, No. 10. pp. 884-906.
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abstract = "RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. OBJECTIVE: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. METHODS AND RESULTS: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTSΔSM22). Hypoxia-induced PH was attenuated in ADAMTSΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8ΔαMHC). ADAMTS8ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. CONCLUSIONS: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.",
author = "Junichi Omura and Kimio Satoh and Nobuhiro Kikuchi and Taijyu Satoh and Ryo Kurosawa and Masamichi Nogi and Tomohiro Ohtsuki and Al-Mamun, {Md Elias} and Siddique, {Mohammad Abdul Hai} and Nobuhiro Yaoita and Shinichiro Sunamura 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, Ohtsuki, T, Al-Mamun, ME, Siddique, MAH, Yaoita, N, Sunamura, S, Miyata, S, Hoshikawa, Y, Okada, Y & Shimokawa, H 2019, 'ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure: A Possible Novel Therapeutic Target', Circulation research, vol. 125, no. 10, pp. 884-906. https://doi.org/10.1161/CIRCRESAHA.119.315398

ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure : A Possible Novel Therapeutic Target. / Omura, Junichi; Satoh, Kimio; Kikuchi, Nobuhiro; Satoh, Taijyu; Kurosawa, Ryo; Nogi, Masamichi; Ohtsuki, Tomohiro; Al-Mamun, Md Elias; Siddique, Mohammad Abdul Hai; Yaoita, Nobuhiro; Sunamura, Shinichiro; Miyata, Satoshi; Hoshikawa, Yasushi; Okada, Yoshinori; Shimokawa, Hiroaki.

In: Circulation research, Vol. 125, No. 10, 25.10.2019, p. 884-906.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure

T2 - A Possible Novel Therapeutic Target

AU - Omura, Junichi

AU - Satoh, Kimio

AU - Kikuchi, Nobuhiro

AU - Satoh, Taijyu

AU - Kurosawa, Ryo

AU - Nogi, Masamichi

AU - Ohtsuki, Tomohiro

AU - Al-Mamun, Md Elias

AU - Siddique, Mohammad Abdul Hai

AU - Yaoita, Nobuhiro

AU - Sunamura, Shinichiro

AU - Miyata, Satoshi

AU - Hoshikawa, Yasushi

AU - Okada, Yoshinori

AU - Shimokawa, Hiroaki

PY - 2019/10/25

Y1 - 2019/10/25

N2 - RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. OBJECTIVE: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. METHODS AND RESULTS: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTSΔSM22). Hypoxia-induced PH was attenuated in ADAMTSΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8ΔαMHC). ADAMTS8ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. CONCLUSIONS: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

AB - RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. OBJECTIVE: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. METHODS AND RESULTS: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTSΔSM22). Hypoxia-induced PH was attenuated in ADAMTSΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8ΔαMHC). ADAMTS8ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. CONCLUSIONS: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

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