title: 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: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Dewei
authors: D
authors: Chen
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Yuyu
authors: Y
authors: Yang
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Xian
authors: X
authors: Cheng
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Fei
authors: F
authors: Fang
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Gang
authors: G
authors: Xu
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Zhibin
authors: Z
authors: Yuan
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Jun
authors: J
authors: Xia
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Hui
authors: H
authors: Kong
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Weiping
authors: W
authors: Xie
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Hong
authors: H
authors: Wang
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.).
authors: Mingming
authors: M
authors: Fang
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.). gyq@mail.tmmu.edu.cn yxu2005@gmail.com.
authors: Yuqi
authors: Y
authors: Gao
authors: From the Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, Ministry of Education (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University (D.C., G.X., Z.Y., Y.G., Y.X.), Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (Y.Y., X.C., F.F., M.F., Y.X.), and Department of Respiratory Medicine, the First Hospital Affiliated (J.X., H.K., W.X., H.W.), Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing, China (M.F.); Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (Y.Y.); and Jiangsu Institute of Nuclear Medicine, Jiangsu, China (X.C.). gyq@mail.tmmu.edu.cn yxu2005@gmail.com.
authors: Yong
authors: Y
authors: Xu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000860:Hypoxia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011669:Pulmonary Wedge Pressure; D012313:RNA / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D014664:Vasodilation
chemical_list: C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D012313:RNA
keywords: cell adhesion molecules; epigenetics; hypertension, pulmonary; hypoxia