Megakaryocytic Leukemia 1 Directs a Histone H3 Lysine 4 Methyltransferase Complex to Regulate Hypoxic Pulmonary Hypertension
Megakaryocytic Leukemia 1 Directs a Histone H3 Lysine 4 Methyltransferase Complex to Regulate Hypoxic Pulmonary Hypertension
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巨核细胞白血病 1 指导组蛋白 H3 赖氨酸 4 甲基转移酶复合物调节缺氧性肺动脉高压
DOI：
10.1161/hypertensionaha.114.04585
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发表时间：
2015-04-01
期刊：
影响因子：
8.3
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Chen, Dewei;Yang, Yuyu;Xu, Yong
由于细胞粘附分子（CAM）的转录激活，血管内皮细胞和循环白细胞之间的相互作用增强，有助于建立促炎环境，从而促进慢性缺氧诱导的肺动脉高压的发病机制。决定 CAM 反式激活的分子开关尚未明确定义。我们的目标是确定转录调节因子巨核细胞白血病 1 (MKL1)（也称为心肌素相关转录因子 A (MRTF-A)）在 CAM 反式激活中的参与及其潜在机制。我们在此报告，与野生型同窝小鼠相比，MKL1/MRTF-A 敲除小鼠在暴露于低氧压力时对缺氧诱导的肺动脉高压的发展具有更强的抵抗力。值得注意的是，敲除小鼠中的 CAM 诱导显着减弱，同时白细胞粘附减少。在培养的血管内皮细胞中，MKL1/MRTF-A 的过度表达增强，而 MKL1/MRTF-A 的消耗则抑制缺氧诱导的 CAM 反式激活。为了应对缺氧，MKL1/MRTF-A 与 CAM 启动子上的 NF-&kgr;B 形成复合物。有趣的是，MKL1/MRTF-A 负责将组蛋白 H3 赖氨酸 4 甲基转移酶复合物募集至 CAM 启动子。最后，组蛋白 H3 赖氨酸 4 甲基转移酶复合物的 2 个关键成分 ASH2 和 WDR5 的内皮特异性沉默可改善小鼠缺氧诱导的肺动脉高压。总之，我们的数据表明，MKL1/MRTF-A 通过协调 CAM 启动子上的关键表观遗传改变，为缺氧诱导的内皮功能障碍提供了关键联系，并有助于缺氧诱导的肺动脉高压的发病机制。
Enhanced interaction between vascular endothelial cells and circulating leukocytes, as a result of transcriptional activation of cell adhesion molecules (CAM), helps establish a proinflammatory milieu contributing to the pathogenesis of chronic hypoxia-induced pulmonary hypertension. The molecular switch that dictates CAM transactivation is not clearly defined. Our goal was to determine the involvement of the transcriptional modulator megakaryocytic leukemia 1 (MKL1), also known as myocardin-related transcription factor A (MRTF-A), in CAM transactivation and the underlying mechanism. We report here that compared with wild-type littermates, MKL1/MRTF-A knockout mice were more resistant to the development of hypoxia-induced pulmonary hypertension when exposed to low oxygen pressure. Notably, CAM induction in knockout mice was significantly attenuated with a concomitant reduction of leukocyte adhesion. In cultured vascular endothelial cells, overexpression of MKL1/MRTF-A enhanced, whereas depletion of MKL1/MRTF-A dampened, hypoxia-induced CAM transactivation. In response to hypoxia, MKL1/MRTF-A formed a complex with NF-&kgr;B on the CAM promoters. Of interest, MKL1/MRTF-A was responsible for recruiting a histone H3 lysine 4 methyltransferase complex to the CAM promoters. Finally, endothelial-specific silencing of ASH2 and WDR5, 2 key components of the histone H3 lysine 4 methyltransferase complex, ameliorated hypoxia-induced pulmonary hypertension in mice. In conclusion, our data suggest that MKL1/MRTF-A, by coordinating key epigenetic alterations on CAM promoters, provides a critical link to hypoxia-induced endothelial malfunction and contributes to the pathogenesis of hypoxia-induced pulmonary hypertension.