A non-thiazolidinedione partial peroxisome proliferator-activated receptor γ ligand inhibits vascular smooth muscle cell growth

Abstract

Several peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione class inhibit vascular smooth muscle cell proliferation. It is not known whether the antiproliferative activity of PPARγ agonists is limited to the thiazolidinedione class and/or is directly mediated through PPARγ-dependent transactivation of target genes. We report here that a novel non-thiazolidinedione partial PPARγ agonist (nTZDpa) attenuates rat aortic vascular smooth muscle cell proliferation. In a transfection assay for PPARγ transcriptional activation, the non-thiazolidinedione partial PPARγ agonist elicited ∼25% of the maximal efficacy of the full PPARγ agonist rosiglitazone. In the presence of the non-thiazolidinedione partial PPARγ agonist, the transcriptional activity of the full agonist, rosiglitazone, was blunted, indicating that the non-thiazolidinedione partial PPARγ agonist inhibits rosiglitazone-induced PPARγ activity. The non-thiazolidinedione partial PPARγ agonist (0.1–10 μM) inhibited vascular smooth muscle cell growth which was accompanied by an inhibition of retinoblastoma protein phosphorylation. Mitogen-induced downregulation of the cyclin-dependent kinase (CDK) inhibitor p27 kip1, and induction of the G1 cyclins cyclin D1, cyclin A, and cyclin E were also attenuated by the non-thiazolidinedione partial PPARγ agonist. Maximal antiproliferative activity of the non-thiazolidinedione partial PPARγ agonist required functional PPARγ as adenovirus-mediated overexpression of a dominant-negative PPARγ mutant partially reversed its inhibition of vascular smooth muscle cell growth. In contrast, overexpression of dominant-negative PPARγ did not reverse the inhibitory effect of the non-thiazolidinedione partial PPARγ agonist on cyclin D1. As the full PPARγ agonist rosiglitazone exhibited no effect on cyclin D1, inhibition of that G1 cyclin by the non-thiazolidinedione partial PPARγ agonist likely occurred through a PPARγ-independent mechanism. These data demonstrate that a non-thiazolidinedione partial PPARγ agonist may constitute a novel therapeutic for proliferative vascular diseases and could provide additional evidence for the important role of PPARγ in regulating vascular smooth muscle cell proliferation.