Involvement of the bone morphogenetic protein system in endothelin-and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Ryutaro Yamanaka, Fumio Otsuka, Kazufumi Nakamura, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Yoshinori Matsumoto, Kengo F. Kusano, Hiroshi Itoh, Hirofumi Makino

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Abstract

Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11ΒHSD2 (11Β-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

Original languageEnglish
Pages (from-to)435-445
Number of pages11
JournalHypertension Research
Volume33
Issue number5
DOIs
Publication statusPublished - May 2010

Fingerprint

Bone Morphogenetic Proteins
Endothelins
Aldosterone
Pulmonary Hypertension
Pulmonary Artery
Smooth Muscle Myocytes
Cell Proliferation
Mineralocorticoid Receptors
Lung
Mitosis
Bone Morphogenetic Protein 7
Angiotensin II
Type II Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein 6
11-beta-Hydroxysteroid Dehydrogenases
Mitogen-Activated Protein Kinase 3
Germ-Line Mutation
JNK Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Mitogen-Activated Protein Kinases

Keywords

  • Aldosterone
  • Bone morphogenetic protein
  • Endothelin
  • Mineralocorticoid receptor
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

@article{2ff649fd4f7f45e28362f0ec7f872969,
title = "Involvement of the bone morphogenetic protein system in endothelin-and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension",
abstract = "Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11ΒHSD2 (11Β-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.",
keywords = "Aldosterone, Bone morphogenetic protein, Endothelin, Mineralocorticoid receptor, Pulmonary arterial hypertension",
author = "Ryutaro Yamanaka and Fumio Otsuka and Kazufumi Nakamura and Misuzu Yamashita and Hiroyuki Otani and Masaya Takeda and Yoshinori Matsumoto and Kusano, {Kengo F.} and Hiroshi Itoh and Hirofumi Makino",
year = "2010",
month = "5",
doi = "10.1038/hr.2010.16",
language = "English",
volume = "33",
pages = "435--445",
journal = "Hypertension Research",
issn = "0916-9636",
publisher = "Nature Publishing Group",
number = "5",

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TY - JOUR

T1 - Involvement of the bone morphogenetic protein system in endothelin-and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

AU - Yamanaka, Ryutaro

AU - Otsuka, Fumio

AU - Nakamura, Kazufumi

AU - Yamashita, Misuzu

AU - Otani, Hiroyuki

AU - Takeda, Masaya

AU - Matsumoto, Yoshinori

AU - Kusano, Kengo F.

AU - Itoh, Hiroshi

AU - Makino, Hirofumi

PY - 2010/5

Y1 - 2010/5

N2 - Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11ΒHSD2 (11Β-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

AB - Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11ΒHSD2 (11Β-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

KW - Aldosterone

KW - Bone morphogenetic protein

KW - Endothelin

KW - Mineralocorticoid receptor

KW - Pulmonary arterial hypertension

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U2 - 10.1038/hr.2010.16

DO - 10.1038/hr.2010.16

M3 - Article

VL - 33

SP - 435

EP - 445

JO - Hypertension Research

JF - Hypertension Research

SN - 0916-9636

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