Worley Joanna R, Baugh Mark D, Hughes David A, Edwards Dylan R, Hogan Aileen, Sampson Mike J, Gavrilovic Jelena
School of Biological Sciences, University of East Anglia, and Bertram Diabetes Research Unit, Norfolk & Norwich University Hospital NHS Trust, Norwich, United Kingdom.
J Biol Chem. 2003 Dec 19;278(51):51340-6. doi: 10.1074/jbc.M310865200. Epub 2003 Oct 8.
The PPAR gamma agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.
过氧化物酶体增殖物激活受体γ激动剂噻唑烷二酮类（TZDs）具有抗炎特性，同时还能提高胰岛素敏感性。这使其治疗范围得以扩大，除了用于治疗2型糖尿病外，还可用于治疗动脉粥样硬化等炎症性疾病。已知TZDs可降低基质金属蛋白酶（MMP）-9在单核细胞/巨噬细胞中的表达，而MMP-9与动脉粥样硬化斑块的不稳定有关。本研究旨在确定ADAM（一种去整合素和金属蛋白酶）和ADAMTS家族的其他金属蛋白酶基因，这些基因受PPARγ或RXR激动剂调控，在2型糖尿病和/或相关动脉粥样硬化中可能具有重要意义。合成的PPARγ激动剂GW7845和天然激动剂15d-PGJ2，仅在存在9-顺式视黄酸的情况下，才能抑制人单核细胞样细胞（THP-1）中由佛波酯（PMA）刺激的MMP-9。定量实时PCR显示，这种降低是在mRNA水平上受到调控的。用PMA刺激THP-1可使ADAMs 8、9和17的表达增加，而ADAM15的表达降低，不过这些ADAMs不受PPARγ或RXR激动剂的调控。添加9-顺式视黄酸可进一步增强PMA诱导的ADAM28表达。与类风湿性关节炎有关的ADAMTS4在THP-1细胞中表达，且在PMA刺激24小时后显著增加。ADAMTS4的表达受到PPARγ和RXR激动剂的抑制，当两种激动剂联合使用时则检测不到其表达。用PPARγ拮抗剂GW9662对THP-1细胞进行预处理表明，PPARγ在MMP-9、ADAMTS4和ADAM28基因表达的调控中发挥着略有不同的作用。这些结果表明，PPARγ和RXR激动剂对单核细胞金属蛋白酶的表达具有复杂的影响，这可能对治疗策略具有重要意义。
