Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats.
Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats.
复制标题
手术引起的海马血管紧张素 II 升高通过 MMP/TIMP 导致老年大鼠血脑屏障破坏
DOI：
10.3389/fncel.2016.00105
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发表时间：
2016
影响因子：
5.3
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Li Z;Mo N;Li L;Cao Y;Wang W;Liang Y;Deng H;Xing R;Yang L;Ni C;Chui D;Guo X
可逆性血脑屏障（BBB）破坏已统一报告在几个动物模型的术后认知功能障碍（POCD）。然而，这种情况发生的确切机制仍不清楚。本研究采用老年大鼠POCD模型，观察了BBB破坏相关分子MMP-2、MMP-9及其内源性组织抑制因子TIMP-1、TIMP-2、TIMP-3的动态变化，并试图建立MMP/TIMP平衡与手术诱导的海马BBB破坏的相关性。我们验证了手术后海马血管紧张素II（Ang II）和Ang II受体1型（AT 1）的表达增加。我们还发现早在术后6 h MMP/TIMP失衡，以及术后24 h BBB通透性增加和Occludin和闭合小带-1（ZO-1）表达减少，以及基底层蛋白层粘连蛋白增加。AT 1拮抗剂坎地沙坦恢复MMP/TIMP平衡，调节Occludin和层粘连蛋白的表达，但不调节ZO-1的表达，从而改善BBB通透性。这些事件伴随着手术诱导的经典核因子-κB（NF-κB）激活级联反应的抑制。然而，AT 1拮抗剂不影响核受体过氧化物酶体增殖物激活受体γ（PPARγ）的表达。总的来说，这些发现表明，手术诱导的Ang II释放通过激活NF-κB信号和破坏下游MMP/TIMP平衡，通过AT 1受体损害BB B的完整性。
Reversible blood-brain barrier (BBB) disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD). Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), as well as three of their endogenous tissue inhibitors of MMP (TIMP-1, -2, -3), and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II) and Ang II receptor type 1 (AT1) after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1), as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB) activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.