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  • Title: Thiazolidinediones prevent PDGF-BB-induced CREB depletion in pulmonary artery smooth muscle cells by preventing upregulation of casein kinase 2 alpha' catalytic subunit.
    Author: Garat CV, Crossno JT, Sullivan TM, Reusch JE, Klemm DJ.
    Journal: J Cardiovasc Pharmacol; 2010 May; 55(5):469-80. PubMed ID: 20147842.
    Abstract:
    BACKGROUND: 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 cyclic adenosine monophosphate response element binding protein (CREB) in PA SMCs stimulates their proliferation and migration in vitro. Platelet-derived growth factor (PDGF) produced in the hypoxic PA wall promotes CREB proteasomal degradation in SMCs via phosphatidylinositol-3-kinase/Akt signaling, which promotes phosphorylation of CREB at 2 casein kinase 2 (CK2) sites. Here we tested whether thiazolidinediones, agents that inhibit hypoxia-induced PA remodeling, attenuate SMC CREB loss. METHODS: Depletion of CREB and changes in casein kinase 2 catalytic subunit expression and activity were measured in PA SMC treated with PDGF. PA remodeling and changes in medial PA CREB and casein kinase 2 levels were evaluated in lung sections from rats exposed to hypoxia for 21 days. RESULTS: 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 alpha' catalytic subunit expression and activity in PA SMCs, and depletion of CK2 alpha' subunit prevented PDGF-stimulated CREB loss. Troglitazone inhibited PDGF-induced CK2 alpha' subunit expression in vitro and rosiglitazone blocked induction of CK2 catalytic subunit expression by hypoxia in PA SMCs in vivo. CONCLUSION: We conclude that thiazolidinediones prevent PA remodeling in part by suppressing upregulation of CK2 and loss of CREB in PA SMCs.
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