Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No.157, West 5th Road, Xi'an, Shaanxi, 710004, People's Republic of China.
Naunyn Schmiedebergs Arch Pharmacol. 2011 Dec;384(6):517-23. doi: 10.1007/s00210-011-0678-y. Epub 2011 Aug 19.
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.
蛋白酶体功能的抑制已被证明能抑制多种类型的细胞增殖；本研究调查这种情况是否也发生在肺动脉平滑肌细胞（PASMCs）中及其潜在机制。血清素诱导 PASMCs 的 DNA 合成增加了 4.27 倍，而这种效应可被预先孵育细胞与 MG132（一种特异性蛋白酶体抑制剂）而被剂量依赖性地阻断。蛋白酶体功能的抑制并未调节血清素触发的促增殖信号通路，如细胞外信号调节激酶 1/2 （ERK1/2 MAPK）和 Ras 同源基因家族成员 A（RhoA）。进一步的研究表明，用血清素处理 PASMCs 可降低 p21（WAF1）蛋白水平，但不影响其转录；用 ERK1/2 MAPK 或 RhoA 级联抑制剂同样可逆转这一作用。此外，在存在血清素的情况下，MG132 呈剂量依赖性地增加 p21（WAF1）的蛋白水平，10μM MG132 可使 p21（WAF1）蛋白水平增加 4.2 倍，而这一作用并非通过增加 p21（WAF1）mRNA 水平介导。更重要的是，siRNA 转染缺失 p21（WAF1）的细胞可消除 MG132 对细胞增殖的抑制作用。我们的研究表明，蛋白酶体抑制引起的 p21（WAF1）蛋白水平的积累特别介导了其对 PASMCs 增殖的抑制作用，而蛋白酶体功能的抑制可能在肺动脉高压的治疗中有潜在价值。
