PPARd agonist GW501516 inhibits PDGF-stimulated pulmonary arterial smooth muscle cell function related to pathological vascular remodeling

Liu G, Li X, Li Y, Tang X, Xu J, Li R, Hao P, Sun Y.
Source: Biomed Res Int.
Publication Date: (2013)
Issue: 2013: 903947
Research Area:
Basic Research
Cells used in publication:
SMC, pul.artery (PASMC), human
Species: human
Tissue Origin: artery
Endothelial, pulmonary artery (HPAEC), human
Species: human
Tissue Origin: artery
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 d in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs). The data showed that PPAR d was the most abundant isoform in HPASMCs. PPAR d was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPAR d by GW501516, a specific PPAR d 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 d may be a potential therapeutic target against the progression of vascular remodeling in PAH.