A non-thiazolidinedione partial peroxisome proliferator-activated receptor γ ligand inhibits vascular smooth muscle cell growth
详细信息 查看全文
- 作者：Bruemmer ; Dennis ; Berger ; Joel P. ; Liu ; Joey ; Kintscher ; Ulrich ; Wakino ; Shu ; Fleck ; Eckart ; et. al.
- 关键词：PPARγ ; (Peroxisome proliferator-activated receptor γ ; ) ; Smooth muscle cell ; vascular ; Cell cycle ; Cyclin D1
- 刊名：European Journal of Pharmacology
- 出版年：2003
- 出版时间：April 18, 2003
- 年：2003
- 卷：466
- 期：3
- 页码：225-234
- 全文大小：371 K
文摘
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 p27kip1, 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.
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 p27kip1, 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.