Thiazolidinediones prevent PDGF-BB-induced CREB depletion in pulmonary artery smooth muscle cells by preventing upregulation of casein kinase 2 alpha' catalytic subunit.
Thiazolidinediones prevent PDGF-BB-induced CREB depletion in pulmonary artery smooth muscle cells by preventing upregulation of casein kinase 2 alpha' catalytic subunit.
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DOI：
10.1097/fjc.0b013e3181d64dbe
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发表时间：
2010-05
影响因子：
3
通讯作者：
Klemm DJ
中科院分区：
文献类型：
--
作者：
Garat CV;Crossno JT Jr;Sullivan TM;Reusch JE;Klemm DJ
暴露于慢性缺氧的动物，在重塑的高血压肺动脉（PAs）中的平滑肌细胞（SMCs）中转录因子CREB减少。PA SMCs中CREB的强制耗尽刺激其体外增殖和迁移。缺氧PA壁中产生的PDGF通过PI3Kinase/Akt信号通路促进SMCs中CREB蛋白酶体降解，从而促进CREB在两个酪蛋白激酶2 （CK2）位点的磷酸化。在这里，我们测试了噻唑烷二酮类药物，抑制缺氧诱导的PA重塑，是否减轻SMC CREB损失。我们发现噻唑烷二酮罗格列酮可预防慢性缺氧大鼠PA重塑和SMC CREB丢失。同样，噻唑烷二酮曲格列酮可阻断PDGF诱导的PA SMC增殖和CREB耗竭。噻唑烷二酮不抑制体内缺氧和体外PDGF对Akt的激活。然而，PDGF诱导了CK2 α ‘催化亚基在PA SMCs中的表达和活性，CK2 α ’亚基的缺失阻止了PDGF刺激的CREB损失。罗格列酮在体外抑制pdgf诱导的CK2 α′亚基表达，在体内阻断缺氧诱导的PA SMCs中CK2 α′亚基表达。我们得出的结论是，噻唑烷二酮部分通过抑制PA SMCs中CK2的上调和CREB的丢失来阻止PA重塑。
The transcription factor CREB is diminished in smooth muscle cells (SMCs) in remodeled, hypertensive pulmonary arteries (PAs) in animals exposed to chronic hypoxia. Forced depletion of CREB in PA SMCs stimulates their proliferation and migration in vitro. PDGF produced in the hypoxic PA wall promotes CREB proteasomal degradation in SMCs via PI3Kinase/Akt signaling, which promotes phosphorylation of CREB at two casein kinase 2 (CK2) sites. Here we tested whether thiazolidinediones, agents that inhibit hypoxia-induced PA remodeling, attenuate SMC CREB loss. We found that the thiazolidinedione rosiglitazone prevented PA remodeling and SMC CREB loss in rats exposed to chronic hypoxia. Likewise, the thiazolidinedione troglitazone blocked PA SMC proliferation and CREB depletion induced by PDGF in vitro. Thiazolidinediones did not repress Akt activation by hypoxia in vivo or by PDGF in vitro. However, PDGF induced CK2 α′ catalytic subunit expression and activity in PA SMCs, and depletion of CK2 α′ subunit prevented PDGF-stimulated CREB loss. Troglitazone inhibited PDGF-induced CK2 α′ subunit expression in vitro and rosiglitazone blocked induction of CK2 catalytic subunit expression by hypoxia in PA SMCs in vivo. We conclude that thiazolidine-diones prevent PA remodeling in part by suppressing upregulation of CK2 and loss of CREB in PA SMCs.