title: Pioglitazone suppresses advanced glycation end product-induced expression of plasminogen activator inhibitor-1 in vascular smooth muscle cells.
abstract: Advanced glycation end products (AGEs) play an important role in vascular complications of diabetes, including fibrinolytic abnormalities. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has recently been shown to reduce circulating plasminogen activator inhibitor-1 (PAI-1) levels in diabetes mellitus. In the present study, we investigated the effects of pioglitazone on the expression of local PAI-1 in rat vascular smooth muscle cells (VSMCs) induced by AGEs and the underlying mechanism. The result showed that AGEs could enhance the PAI-1 expression by 5.1-fold in mRNA and 2.7-fold in protein level, as evaluated by real-time RT-PCR and Western blotting, respectively. Pioglitazone was found to down-regulate the AGE-stimulated PAI-1 expression in VSMCs. However, these inhibitory effects were partially attenuated by the PPARγ antagonist, GW9662. Furthermore, we found that AGEs induced a rapid increase in phosphorylation and activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). The ERK kinase inhibitor, U0126, partially prevented the induction of PAI-1 by AGEs. Moreover, pioglitazone was also found to inhibit the phosphorylation of ERK1/2. Taken together, it was concluded that pioglitazone could inhibit AGE-induced PAI-1 expression, which was mediated by the ERK1/2 and PPARγ pathways. Our findings suggested pioglitazone had a therapeutic potential in improving fibrinolytic activity, and consequently preventing thromboembolic complications of diabetes and cardiovascular disease.
authors.affiliation: Department of Cardiology, Institute for Cardiovascular Medicine, Zhongda Hospital of Southeast University, Nanjing 210009, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Yuan
authors.forename: Naifeng
authors.initials: N
authors.lastname: Liu
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D048049:Extracellular Signal-Regulated MAP Kinases; D000077205:Pioglitazone