Pioglitazone suppresses advanced glycation end product-induced expression of plasminogen activator inhibitor-1 in vascular smooth muscle cells

Xiaochen Yuan^{a, b},
Naifeng Liu^{a
, ,}

a.
Department of Cardiology, Institute for Cardiovascular Medicine, Zhongda Hospital of Southeast University, Nanjing 210009, China
b.
Department of Cardiology, Institute for Cardiovascular Medicine of Southeast University, the First People’s Hospital of Yangzhou, Yangzhou 225001, China

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Corresponding author: E-mail address: yz_yxc@sohu.com (Naifeng Liu)

摘要

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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.
- AGEs /
- PPARγ /
- Pioglitazone /
- Plasminogen activator inhibitor-1

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