title: PPARδ agonist GW501516 inhibits PDGF-stimulated pulmonary arterial smooth muscle cell function related to pathological vascular remodeling.
abstract: Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Growth factors, cytokines, and lipid mediators are involved in this remodeling process. Recent reports suggest that the peroxisome proliferator-activated receptors (PPARs) play important roles in the regulation of cell growth and differentiation as well as tissue wounding and repair. In this study, we examined the role of PPAR δ in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs). The data showed that PPAR δ was the most abundant isoform in HPASMCs. PPAR δ was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPAR δ by GW501516, a specific PPAR δ ligand, significantly inhibited PDGF-induced proliferation in HPASMCs. The inhibitory effect of GW501516 on HPASMCs was associated with decreased expression of cyclin D1, cyclin D3, CDK2, and CDK4 as well as increased expression of the cell cycle inhibitory genes G0S2 and P27(kip1). Pretreatment of HPASMCs with GW501516 significantly inhibited PDGF-induced cell migration and collagen synthesis. GW501516 also significantly attenuated TNF-mediated expression of MCP-1. These results suggest that PPAR δ may be a potential therapeutic target against the progression of vascular remodeling in PAH.
authors.affiliation: Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Liu
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Hao
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Sun
mesh_terms: D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D065627:Familial Primary Pulmonary Hypertension; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C425931:GW 501516; D047494:PPAR delta; D010982:Platelet-Derived Growth Factor; D013844:Thiazoles; D003094:Collagen