Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 34, Issue 5, Pages 618-623Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.34.618
Keywords
pioglitazone; advanced glycation end product; vascular smooth muscle cell; peroxisome proliferator activated receptor gamma; proliferation
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Funding
- National Natural Science foundation of China [30070300, 81070096]
- Natural Science Foundation of Jiangsu Province [BK2008220, BK2010324]
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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 (PPAR gamma) 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 PPAR gamma. Pretreatment of pioglitazone not only prevented the down-regulation of PPAR gamma, 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 PPAR gamma expression and inhibiting ROS/ERK1/2 signaling pathway.
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