title: Inhibition of reactive oxygen species/extracellular signal-regulated kinases pathway by pioglitazone attenuates advanced glycation end products-induced proliferation of vascular smooth muscle cells in rats.
abstract: Advanced glycation end products (AGEs) have been shown to induce the proliferation of vascular smooth muscle cells (VSMCs) and contribute to atherogenesis and diabetes. In the present study, we investigated the effects of pioglitazone, a peroxisome proliferator activated receptor gamma (PPARγ) agonist, on AGE-induced rat VSMC growth and the underlying mechanism. In cultured rat VSMCs, AGE treatment induced VSMC proliferation in time- and dose-dependent manner, while down-regulated the expression of PPARγ. Pretreatment of pioglitazone not only prevented the down-regulation of PPARγ, but inhibited VSMC proliferation and prevented S-phase entry of cell via a G0-G1 block in the presence of AGEs. Western blotting analysis showed that AGE treatment potentiated to activate extracelluar signal-regulated kinases (ERK1/2) by the induction of intracellular reactive oxygen species (ROS) production, since ROS scavenger N-acetyl-L-cysteine pretreatment significantly inhibited AGE-induced ERK1/2 activation. Further, pretreatment with either N-acetyl-L-cysteine or the inhibitor of ERK1/2 activation suppressed AGE-induced proliferation of VSMCs, suggesting a role of ROS/ERK1/2 signaling. Notably, we demonstrated that pretreatment of pioglitazone significantly attenuated AGE-induced ROS and ERK1/2 activation. Collectively, these results suggest that pioglitazone inhibits AGE-induced VSMC proliferation via increasing PPARγ expression and inhibiting ROS/ERK1/2 signaling pathway.
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease of Southeast University, The First People's Hospital of Yangzhou, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Yuan
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kaizheng
authors.initials: K
authors.lastname: Gong
authors.forename: Pei
authors.initials: P
authors.lastname: Zhao
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qin
authors.forename: Naifeng
authors.initials: N
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D048049:Extracellular Signal-Regulated MAP Kinases; D000077205:Pioglitazone