Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs

Jun Zhang, Wenju Lu, Yuqin Chen, Qian Jiang, Kai Yang, Meichan Li, Ziyi Wang, Xin Duan, Lei Xu, Haiyang Tang, Dejun Sun, Jian Wang

Research output: Contribution to journalArticle

Abstract

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 Ca2+ concentration ([Ca2+]i) and store-operated Ca2+ 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 [Ca2+] 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 [Ca2+]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregu-lated 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-ɤ 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-[Ca2+]i signaling axis in PASMCs.

Original languageEnglish (US)
Pages (from-to)C482-C497
JournalAmerican Journal of Physiology - Cell Physiology
Volume311
Issue number3
DOIs
StatePublished - 2016
Externally publishedYes

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Keywords

  • Bortezomib
  • Canonical transient receptor potential
  • Intracellular calcium concentration
  • Pulmonary hypertension
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cell Biology

Cite this

Zhang, J., Lu, W., Chen, Y., Jiang, Q., Yang, K., Li, M., Wang, Z., Duan, X., Xu, L., Tang, H., Sun, D., & Wang, J. (2016). Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs. American Journal of Physiology - Cell Physiology, 311(3), C482-C497. https://doi.org/10.1152/ajpcell.00324.2015