Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells

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 p21 ^WAF1 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 p21 ^WAF1 in a dose-dependent manner in the presence of serotonin, 10 μM MG132 led to a 4.2-fold increase in p21 ^WAF1 protein level, and this effect was not mediated by increasing p21 ^WAF1 mRNA level. More importantly, cell lacking p21 ^WAF1 by siRNA transfection abolished the inhibitive effect of MG132 on cells proliferation. Our study suggests that accumulation of p21 ^WAF1 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.