p53 protects against LPS-induced lung endothelial barrier dysfunction
p53 protects against LPS-induced lung endothelial barrier dysfunction
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DOI：
10.1152/ajplung.00334.2014
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发表时间：
2015-04-15
影响因子：
4.9
通讯作者：
Catravas, John D.
中科院分区：
文献类型：
--
作者：
Barabutis, Nektarios;Dimitropoulou, Christiana;Catravas, John D.
针对心脏和血管疾病的新疗法可能会从Hsp 90抑制剂的开发中出现。几项独立研究表明，这些药物在人体组织中具有强效抗炎活性。其在血管系统中保护作用的分子机制尚不清楚。本研究表明，转录因子p53，热休克蛋白90的客户端蛋白，是至关重要的维持血管的完整性，再次保护LPS诱导的内皮屏障功能障碍，并参与介导的抗炎活性的热休克蛋白90抑制剂在肺组织。通过siRNA沉默p53降低了跨内皮阻力（内皮屏障功能的量度）。p53抑制剂pifithrin诱导了类似的作用，其也增强了LPS诱导的人肺微血管内皮细胞（HLMVEC）的高通透性。另一方面，nutlin诱导的p53抑制LPS诱导的血管屏障功能障碍。LPS降低肺组织中p53的表达，这种作用可被Hsp 90抑制剂阻断。此外，Hsp 90抑制剂17-烯丙基-氨基-去甲氧基-格尔德霉素抑制LPS诱导的HLMVEC中p53负调节因子MDMX的过表达以及p53和MDM 2（另一种p53负调节因子）磷酸化。两种负性p53调节因子在体内均被LPS下调。化学诱导的p53过表达导致LPS诱导的RhoA激活和MLC 2磷酸化的抑制，而p53抑制引起相反的效果。这些观察结果揭示了Hsp 90抑制剂抗炎作用的新机制，即，转录因子p53的诱导，这反过来又可以在体内和体外协调强有力的血管抗炎反应。
New therapies toward heart and blood vessel disorders may emerge from the development of Hsp90 inhibitors. Several independent studies suggest potent anti-inflammatory activities of those agents in human tissues. The molecular mechanisms responsible for their protective effects in the vasculature remain unclear. The present study demonstrates that the transcription factor p53, an Hsp90 client protein, is crucial for the maintenance of vascular integrity, protects again LPS-induced endothelial barrier dysfunction, and is involved in the mediation of the anti-inflammatory activity of Hsp90 inhibitors in lung tissues. p53 silencing by siRNA decreased transendothelial resistance (a measure of endothelial barrier function). A similar effect was induced by the p53 inhibitor pifithrin, which also potentiated the LPS-induced hyperpermeability in human lung microvascular endothelial cells (HLMVEC). On the other hand, p53 induction by nutlin suppressed the LPS-induced vascular barrier dysfunction. LPS decreased p53 expression in lung tissues and that effect was blocked by pretreatment with Hsp90 inhibitors both in vivo and in vitro. Furthermore, the Hsp90 inhibitor 17-allyl-amino-demethoxy- geldanamycin suppressed the LPS-induced overexpression of the p53 negative regulator MDMX as well as p53 and MDM2 (another p53 negative regulator) phosphorylation in HLMVEC. Both negative p53 regulators were downregulated by LPS in vivo. Chemically induced p53 overexpression resulted in the suppression of LPS-induced RhoA activation and MLC2 phosphorylation, whereas p53 suppression caused the opposite effects. These observations reveal new mechanisms for the anti-inflammatory actions of Hsp90 inhibitors, i.e., the induction of the transcription factor p53, which in turn can orchestrate robust vascular anti-inflammatory responses both in vivo and in vitro.