Modulation of PPARα expression and inflammatory interleukin-6 production by chronic glucose increases monocyte/endothelial adhesion
Modulation of PPARα expression and inflammatory interleukin-6 production by chronic glucose increases monocyte/endothelial adhesion
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DOI：
10.1161/01.atv.zhq0504.2260
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发表时间：
2004-05-01
影响因子：
8.7
通讯作者：
Hedrick, CC
中科院分区：
文献类型：
--
作者：
Srinivasan, S;Hatley, ME;Hedrick, CC
Objective - We have previously reported increased monocyte adhesion to human aortic endothelial cells (HAECs) cultured in 25 mmol/L glucose (HG) compared with normal glucose (NG) (5.5 mmol/L). In this study, we explored mechanisms that contribute to increased monocyte adhesion by elevated glucose.Methods and Results - We found that HAECs cultured in HG have increased production of the chemokine interleukin-6 (IL-6). We examined whether IL-6 directly modulated monocyte adhesion to EC. Inhibition of IL-6 using a neutralizing antibody significantly reduced glucose-mediated monocyte adhesion by 50%, and addition of IL-6 directly to human EC stimulated monocyte adhesion. PPARalpha has been reported to negatively regulate expression of IL-6 in vascular cells, so we examined PPARalpha-associated signaling in EC. A known PPARalpha agonist, Wy14,643, prevented glucose-mediated IL-6 production by EC and reduced glucose-mediated monocyte adhesion by 40%. HG-cultured HAEC had a 50% reduction in expression of PPARalpha compared with control EC. Primary aortic EC isolated from PPARalpha knockout ( KO) mice showed increased monocyte adhesion compared with EC isolated from control mice. PPARalpha KO EC also had increased production of IL-6. Finally, we measured IL-6 levels in diabetic db/db mice and found significant 6-fold elevations in IL-6 levels in db/db EC.Conclusions - These data indicate that IL-6 production is increased in diabetes and contributes to early vascular inflammatory changes. PPARalpha protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production.
