Activation of PPARγ inhibits HDAC1-mediated pulmonary arterial smooth muscle cell proliferation and its potential mechanisms

Abstract

The downstream targets of histone deacetylase 1 (HDAC1) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and it is also unknown whether activation of peroxisome proliferator-activated receptor γ (PPARγ) modulates HDAC1 and its down-stream targets in PASMCs. The present study aims to address these issues. Our results showed that PDGF dose- and time-dependently induced PASMC proliferation, and this was accompanied by an increase of HDAC1 and cyclin-dependent kinase 4 (CDK4) protein expression as well as a reduction of microRNA-124 (miR-124). Pre-silencing of HDAC1 with small interfering RNA (siRNA) abolished PDGF-induced miR-124 down-regulation, CDK4 protein up-regulation, and PASMC proliferation. In addition, over-expression of miR-124 reversed CDK4 protein elevation and PASMC proliferation caused by PDGF. We further found that pre-incubation of PASMCs with pioglitazone, an agonist of PPARγ receptors, significantly increased PPARγ expression and activity, and blocked PDGF-stimulated cell proliferation by regulating HDAC1-mediated miR-124 and CDK4 expression. Our study indicates that HDAC1/miR-124/CDK4 axis plays an important role in PDGF-induced PASMC proliferation, and activation of PPARγ inhibits PASMC proliferation by acting on HDAC1 pathway.

Keywords: CDK4; HDAC1; PPARγ; Pulmonary arterial smooth muscle cell; miR-124.