Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs
Copyright © 2016 the American Physiological Society..
The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:311 |
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| Enthalten in: |
American journal of physiology. Cell physiology - 311(2016), 3 vom: 01. Sept., Seite C482-97 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Jun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.06.2017 Date Revised 28.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1152/ajpcell.00324.2015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM262396181 |
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| 245 | 1 | 0 | |a Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs |
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| 500 | |a Date Revised 28.07.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016 the American Physiological Society. | ||
| 520 | |a The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a bortezomib | |
| 650 | 4 | |a canonical transient receptor potential | |
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| 650 | 7 | |a Calcium |2 NLM | |
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| 700 | 1 | |a Lu, Wenju |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuqin |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Meichan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ziyi |e verfasserin |4 aut | |
| 700 | 1 | |a Duan, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Haiyang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Dejun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jian |e verfasserin |4 aut | |
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