Megakaryocytic leukemia 1 directs a histone H3 lysine 4 methyltransferase complex to regulate hypoxic pulmonary hypertension.

Abstract

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-κB 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.

• Authors: Dewei Chen, Yuyu Yang, Xian Cheng, Fei Fang, Gang Xu, Zhibin Yuan, Jun Xia, Hui Kong, Weiping Xie, Hong Wang, Mingming Fang, Yuqi Gao, Yong Xu
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 65 Issue 4 Pg. 821-33 (Apr 2015) ISSN: 1524-4563 [Electronic] United States
• PMID: 25646298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Mrtfa protein, mouse
• Trans-Activators
• RNA

Topics

• Animals
• Disease Models, Animal
• Endothelium, Vascular (metabolism, physiopathology)
• Epigenesis, Genetic
• Gene Expression Regulation
• Hypertension, Pulmonary (etiology, genetics, metabolism)
• Hypoxia (etiology, genetics, metabolism)
• Leukemia, Megakaryoblastic, Acute (complications, genetics, metabolism)
• Mice
• Mice, Knockout
• Polymerase Chain Reaction
• Pulmonary Wedge Pressure
• RNA (genetics)
• Trans-Activators (biosynthesis, genetics)
• Transcriptional Activation
• Vasodilation