PPARγ activation suppresses the expression of MMP9 by downregulating NF-κB post intracerebral hemorrhage
PPARγ activation suppresses the expression of MMP9 by downregulating NF-κB post intracerebral hemorrhage
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DOI：
10.1016/j.neulet.2021.135770
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发表时间：
2021-03-25
影响因子：
2.5
通讯作者：
Wu, Guofeng
中科院分区：
文献类型：
--
作者：
Luo, Xingmei;Wu, Jing;Wu, Guofeng
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）在保护脑损伤后免受炎症和氧化应激中是至关重要的。我们以前曾报道过罗格列酮，一种过氧化物酶体增殖物激活受体γ激动剂，能有效地防止小胶质细胞凋亡，并通过抑制基质金属蛋白酶-9（MMP-9）的表达来改善脑出血后神经元的损伤。然而，连接PPAR γ如何降低MMP 9的分子机制仍然未知。在此，我们假设PPAR γ通过抑制核因子κ B（NF-κ B B）下调出血后MMP 9的表达，NF-κ B是MMP基因的上游调节因子，也是参与免疫和神经炎症反应控制的关键转录因子。我们在体内和体外均发现，脑出血后PPAR γ表达显著下调，NF-κ B B和MMP 9显著增加。使用罗格列酮激活PPAR γ可降低NF-κ B和MMP 9的表达，而使用PPAR γ拮抗剂GW 9662则可观察到相反的作用。此外，通过JSH-23抑制NF-κ B也抑制MMP 9的表达，对PPAR γ的影响有限。进一步的研究显示NF-κ B分别与PPAR γ和MMP 9显著共定位。最后，直接相互作用的NF-κ B与过氧化物酶体增殖物激活受体γ和基质金属蛋白酶9基因也证实，分别通过蛋白质和染色质免疫沉淀。这些结果提示NF-γ B在介导PPAR γ降低MMP 9中的作用，可能为脑出血提供新的治疗靶点。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is critical in protecting against inflammatory and oxidative stresses post brain injury. We have previously reported that rosiglitazone, an agonist of PPAR gamma, was effective to prevent microglia from apoptosis and ameliorate neuronal injuries post intracerebral hemorrhage (ICH) with suppression of matrix metalloproteinase-9 (MMP9) expression. However, molecular mechanisms linking how PPAR gamma decreases MMP9 remain unknown. Here, we hypothesize that PPAR gamma downregulates MMP9 expression post hemorrhage by inhibiting nuclear factor kappa B (NF-kappa B), an upstream regulator of MMPs gene and also key transcription factor involved in the control of immune and neuroinflammatory responses. We found both in vivo and in vitro that PPAR gamma was significantly downregulated post ICH with prominent increases of NF-kappa B and MMP9. Activation of PPAR gamma using rosiglitazone decreased the expression of both NF-kappa B and MMP9, while reversed effects were observed when administrating the PPAR gamma antagonist GW9662. Besides, inhibiting NF-kappa B by JSH-23 also suppressed the expression of MMP9, with only limited effect on PPAR gamma. Further studies revealed prominent colocalizations of NF-kappa B with PPAR gamma and MMP9, respectively. Finally, direct interactions of NF-kappa B with PPAR gamma and MMP9 gene were also confirmed, respectively, by protein and chromatin immunoprecipitations. These results suggested a role of NF-gamma B in mediating the reduction of MMP9 by PPAR gamma, potentially providing a new therapeutic target for brain hemorrhage.