Thiazolidinediones Prevent PDGF-BB-induced CREB Depletion in Pulmonary Artery Smooth Muscle Cells by Preventing Upregulation of Casein Kinase 2 α′ Catalytic Subunit

Abstract

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.

Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB

“…This is in line with the observation of increased PDGF-BB levels following hypoxic challenge that are associated with a decrease of CREB expression 36. PDGF-BB has been described to be a target of HIF-1 gene transcription37 and members of the CREB family have several binding sites within the hepcidin promoter and CREB-H is known to be a pivotal inducer of hepcidin expression 17.…”

Targeting mitochondria to restore failed adaptation to exercise in diabetes

“…CREB content and nuclear localization are decreased in vascular diseases including diabetes, dyslipidaemia, hypertension, aging and pulmonary hypertension [9,21,35]. In the light of the impact of CREB on mitochondrial function, we evaluated the mitochondrial content and function in diabetic rodent models and observed decreased mitochondrial protein profiles and enzyme activities [30].…”

Implication of PDGF signaling in cigarette smoke-induced pulmonary arterial hypertension in rat

“…It is well documented that cigarette smoke (CS) is a highly risky factor inducing PAH (Han et al, 2010;Wright, Levy, and Churg 2005) through pulmonary arterial remodeling featured with blood vessel wall thickening as the result of smooth muscle cell (SMC) proliferation, as well as increased deposition of extracellular matrix (e.g. collagen) (Garat et al, 2010;Jeffery and Wanstall 2001;Sakao, Tatsumi, and Voelkel 2010). However, the molecular mechanism of CS-induced PAH remains largely unknown.…”