Abstract
Inhibition of proteasome function has been shown to suppress several types of cells proliferation; this study investigates whether this also occurs in pulmonary artery smooth muscle cells (PASMCs) and its potential mechanisms. Serotonin induced 4.27-fold increase in DNA synthesis in PASMCs, and this effect was dose-dependently blocked by prior incubation of cells with MG132, a specific proteasome inhibitor. Inhibition of proteasome function did not modulate serotonin-triggered pro-proliferation signaling pathways, such as extracellular signal-regulated mitogen-activated protein kinase (ERK1/2 MAPK) and Ras homolog gene family member A (RhoA). Further study indicated that treatment of PASMCs with serotonin reduced p21WAF1 protein level but not its transcription; this was reversed by inhibiting ERK1/2 MAPK or RhoA cascade equally. In addition, MG132 increased the protein level of p21WAF1 in a dose-dependent manner in the presence of serotonin, 10 μM MG132 led to a 4.2-fold increase in p21WAF1 protein level, and this effect was not mediated by increasing p21WAF1 mRNA level. More importantly, cell lacking p21WAF1 by siRNA transfection abolished the inhibitive effect of MG132 on cells proliferation. Our study suggests that accumulation of p21WAF1 protein level caused by proteasome inhibition particularly mediated its inhibitive effect on PASMCs proliferation, and inhibition of proteasome function might have potential value in the treatment of pulmonary hypertension.
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Acknowledgments
This work was supported by Chinese National Science Foundation (30871116) and the start-up package to Manxiang Li from the Second Affiliated Hospital of Medical College of Xi'an Jiaotong University, People’s Republic of China.
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Li, M., Dong, X., Liu, Y. et al. Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells. Naunyn-Schmiedeberg's Arch Pharmacol 384, 517–523 (2011). https://doi.org/10.1007/s00210-011-0678-y
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DOI: https://doi.org/10.1007/s00210-011-0678-y