Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction.
Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction.
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DOI：
10.1186/s13054-015-0943-4
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发表时间：
2015-05-11
期刊：
影响因子：
--
通讯作者：
Denisenko O
中科院分区：
文献类型：
--
作者：
Bomsztyk K;Mar D;An D;Sharifian R;Mikula M;Gharib SA;Altemeier WA;Liles WC;Denisenko O
Tie 2/血管生成素（Tie 2/Ang）和血管内皮生长因子受体-配体系统（VEGFR/VEGF）在微血管内皮功能的调节中起重要作用。这些基因在脓毒症过程中的下调与脓毒症相关的微血管渗漏和多器官功能障碍综合征的发病机制有关。脓毒症中血管生成基因失调的机制还不清楚。采用Western blot、逆转录-聚合酶链反应和多重染色质免疫沉淀平台（Matrix ChIP）研究急性肺损伤诱导脓毒症（ALI-脓毒症）小鼠模型中血清白蛋白渗漏、基因表达变化和相关表观遗传学改变。实验性ALI脓毒症诱导肺、肾和肝中微血管渗漏和Angpt 1（Ang 1）、Tek（Tie 2）和Kdr（Vegfr 2或Flk-1）基因表达下调。这些变化与这些基因的RNA聚合酶II密度降低相关，在肺中观察到最大的反应。在所有检查的组织中，ALI脓毒症降低了这些位点的转录允许组蛋白H3赖氨酸乙酰化（H3 KAc）水平。仅在肺中检测到允许的H3 K4 m3和H3 Km 2标记的减少。相比之下，在所有组织中仅观察到转录抑制性组蛋白修饰（H3 K27 m3、H3 K9 m2、H3 K9 m3和H4 K20 m3）的最小变化。我们的研究结果表明，在Angpt 1，Tek和Kdr的转录允许的减少，而不是转录抑制的增加，组蛋白修饰是一种系统性的，而不是肺限制性的，反应，涉及实验性ALI脓毒症的关键终末器官。鉴于呼吸机相关性肺炎是危重患者脓毒症的主要原因，阐明脓毒症期间介导表观遗传学改变的机制为脓毒症诱导的微血管渗漏和随后的终末器官损伤/功能障碍的发病机制提供了基本的新见解。本文的在线版本（doi：10.1186/s13054-015-0943-4）包含补充材料，可供授权用户使用。
The Tie2/angiopoietin (Tie2/Ang) and vascular endothelial growth factor receptor-ligand systems (VEGFR/VEGF) are recognized to play important roles in the regulation of microvascular endothelial function. Downregulation of these genes during sepsis has been implicated in the pathogenesis of sepsis-related microvascular leak and multiple organ dysfunction syndrome. Mechanisms responsible for dysregulation of angiogenic genes in sepsis are poorly defined. Western blot, reverse transcription-polymerase chain reaction, and multiplex chromatin immunoprecipitation platform (Matrix ChIP) were used to investigate serum albumin leak, changes in gene expression, and associated epigenetic alterations in a murine model of acute lung injury-induced sepsis (ALI-sepsis). Experimental ALI-sepsis induced microvascular leak and downregulation of expression of Angpt1 (Ang1), Tek (Tie2), and Kdr (Vegfr2 or Flk-1) genes in the lung, kidney, and liver. These changes correlate with a decrease in RNA polymerase II density at these genes, and the greatest response was observed in the lung. ALI-sepsis reduced levels of transcription-permissive histone H3 lysine acetylation (H3KAc) at these loci in all examined tissues. Decreases in permissive H3K4m3 and H3Km2 marks were detected only in the lung. In contrast, only minimal alterations in transcription-repressive histone modifications (H3K27m3, H3K9m2, H3K9m3, and H4K20m3) were observed in all tissues. Our results demonstrate that decreases in transcription-permissive, but not increases in transcription-repressive, histone modifications at Angpt1, Tek, and Kdr are a systemic, rather than a lung-restricted, response, involving key end-organs in experimental ALI-sepsis. Given that ventilator-associated pneumonia is a major cause of sepsis in critically ill patients, elucidation of mechanisms mediating epigenetic alterations during sepsis provides fundamental new insights into the pathogenesis of sepsis-induced microvascular leak and subsequent end-organ injury/dysfunction. The online version of this article (doi:10.1186/s13054-015-0943-4) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Chakraborty, Subhankar;Kaur, Sukhwinder;Guha, Sushovan;Batra, Surinder K.
通讯作者：
Batra, Surinder K.
影响因子：
8.8
作者：
David S;Mukherjee A;Ghosh CC;Yano M;Khankin EV;Wenger JB;Karumanchi SA;Shapiro NI;Parikh SM
通讯作者：
Parikh SM
影响因子：
3.2
作者：
Lee, Warren L.;Liles, W. Conrad
通讯作者：
Liles, W. Conrad
影响因子：
3.7
作者：
Bomsztyk K;Flanagin S;Mar D;Mikula M;Johnson A;Zager R;Denisenko O
通讯作者：
Denisenko O
影响因子：
7.2
作者：
Jeltsch, Michael;Leppanen, Veli-Matti;Alitalo, Kari
通讯作者：
Alitalo, Kari