title: Multiple Signaling Pathways Contribute to the Thrombin-induced Secretory Phenotype in Vascular Smooth Muscle Cells.
abstract: We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
authors.forename: Younghae
authors.initials: Y
authors.lastname: Son
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea.
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
authors.forename: Byung-Yong
authors.initials: BY
authors.lastname: Rhim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
keywords: CCL11; Secretory phenotype; Signaling pathway; Thrombin; Vascular smooth muscle cell