Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation
Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation
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DOI：
10.1165/ajrcmb.16.5.9160841
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发表时间：
1997-05-01
影响因子：
6.4
通讯作者：
Posada, J
中科院分区：
文献类型：
--
作者：
Whelchel, A;Evans, J;Posada, J
内皮素是一种小肽，是一种有效的支气管收缩剂，气道平滑肌（ASM）的有丝分裂原，并被认为参与哮喘的发病机制。为了了解内皮素如何刺激培养的ASM细胞增殖，我们评估了丝裂原活化蛋白（MAP）激酶激活和细胞增殖之间的关系。内皮素是MAP激酶细胞外调节激酶2（ERK2）亚组的有效刺激剂，ERK2的激活与大鼠ASM细胞的增殖密切相关。使用MEK（MAP或ERK激酶）的小分子抑制剂PD98059来确定ERK 2活化在导致细胞增殖的内皮素刺激的信号转导途径中的作用。虽然PD98059显著抑制内皮素激活ERK的能力，但该药物似乎不影响体外活化的MEK突变体或ERK的催化活性。这些数据表明，PD98059抑制ASM细胞中ERK 2通路的机制可能涉及抑制MEK活化。最终导致ERK 2激活的内皮素信号转导途径依赖于蛋白激酶C（PKC），因为PKC的耗竭显著抑制内皮素激活ERK 2的能力。综上所述，这些数据表明ERK的激活是内皮素信号转导途径中的关键终点，因为抑制这种激酶抑制内皮素诱导的ASM细胞增殖。
Endothelin is a small peptide that is a potent bronchoconstrictor, mitogen for airway smooth muscle (ASM), and is believed to be involved in the pathogenesis of asthma. To understand how endothelin stimulates the proliferation of ASM cells in culture, we evaluated the relationship between mitogen activated protein (MAP) kinase activation and cell proliferation. Endothelin is a potent stimulator of the extracellular regulated kinase 2 (ERK2) subgroup of MAP kinases, and ERK2 activation was tightly correlated with the proliferation of rat ASM cells. PD98059, a small molecule inhibitor of MEK (MAP or ERK kinase) was used to establish the role of ERK2 activation in the endothelin-stimulated signal transduction pathway leading to cell proliferation. While PD98059 significantly inhibited the ability of endothelin to activate ERK, the drug did not appear to effect the catalytic activity of an activated MEK mutant, or ERK in vitro. The data suggest that the mechanism of PD98059 inhibition of the ERK2 pathway in ASM cells may involve inhibition of MEK activation. The endothelin signal transduction pathway that culminates in ERK2 activation was dependent on protein kinase C (PKC), since depletion of PKC significantly inhibited the ability of endothelin to activate ERK2. Taken together, the data imply that activation of ERK is a critical endpoint in the endothelin signal transduction pathway since inhibition of this kinase inhibits endothelin-induced ASM cell proliferation.