Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4
Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4
复制标题
DOI：
10.1523/jneurosci.2897-08.2008
复制
发表时间：
2008-11-19
影响因子：
5.3
通讯作者：
Chen, Hsiao-Huei
中科院分区：
文献类型：
--
作者：
Schock, Sarah C.;Xu, Jin;Chen, Hsiao-Huei
中风后过氧化物酶体增殖物激活受体-γ (PPARγ) 信号的激活可能会减轻脑损伤，但这种效果取决于受体和辅助因子的水平。在这里，我们发现 PPAR γ 信号传导保护神经元免受缺血性损伤的直接作用需要一种新的辅助因子 LMO4，因为这种作用在 LMO4 缺失的皮质神经元中消失了。在前脑神经元中 LMO4 被消除的 CaMKII α Cre/LMO4loxP 小鼠中，PPAR γ 激动剂也未能减少短暂局灶性缺血后的脑梗塞。在 LMO4 缺失的皮质神经元中表达 LMO4 可挽救 PPAR γ 保护作用。 PPAR γ 信号传导激活抗氧化基因 SOD2 的启动子，此过程需要 LMO4。添加超氧化物歧化酶模拟物 MnTBAP [锰(III)四(4-苯甲酸)卟啉]绕过了 PPAR γ 信号传导的缺陷，能够直接拯救 LMO4 缺失的皮质神经元免受缺血性损伤。与 LMO4 一样，神经元中的 PPAR γ 和 PGC1 α（PPAR γ 共激活剂 1 α）水平会因缺氧应激而升高，而 LMO4 的缺失会损害它们的上调。免疫共沉淀和哺乳动物双杂交分析表明，LMO4 以配体依赖性方式与 PPAR γ 相互作用。 LMO4 部分地通过促进 RXR α（类视黄醇 X 受体-α）与 PPAR γ 的结合以及增加 PPAR γ 与其靶 DNA 序列的结合来增强 PPAR γ 依赖性基因激活。总之，我们的结果确定 LMO4 是神经元中 PPAR γ 信号传导所需的重要缺氧诱导辅助因子。因此，中风后 LMO4 表达的上调可能是神经元存活的重要决定因素。
Activation of peroxisome proliferator-activated receptor-gamma (PPAR gamma) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPAR gamma signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPAR gamma agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKII alpha Cre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPAR gamma-protective effect. PPAR gamma signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [ manganese(III) tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPAR gamma signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPAR gamma and PGC1 alpha(PPAR gamma coactivator 1 alpha) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed thatLMO4interacts in a ligand-dependent manner with PPAR gamma. LMO4augments PPAR gamma-dependent gene activation, in part, by promoting RXR alpha (retinoid X receptor-alpha) binding to PPAR gamma and by increasing PPAR gamma binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPAR gamma signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.